Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This application is a divisional of 17/207,101, issued as US Patent No. 11,634,700, which is a divisional of 16/025,261, now issued as US Patent No. 10,961,525.
The amendment filed on November 6, 2025 has been entered.
Election/Restrictions
Applicant elected with traverse of Group VI with a species election of the mutant hyperactive TET enzyme encoded by SEQ ID NO:146 and 147 in the reply filed on May 24, 2024. In view of the amendment of claim 10, the Restriction Requirement mailed on March 26, 2024 was withdrawn.
However, the application contained claims directed to the following patentably distinct species: mutant TET enzymes. Applicant was required to elect ONE mutant TET enzyme by (1) identifying parent TET enzyme and identifying all amino acid modifications made in said parent TET enzyme or (2) identifying the sequence identifier of the mutant TET enzyme. of the mutant TET enzyme.
During telephone conversation with Kathleen D. Rigaut on June 27, 2024, a provisional election was made with traverse to prosecute the invention of the species mutant TET enzyme encoded by SEQ ID NO:147. The polynucleotide of SEQ ID NO:147 encodes a mutant of human TET2 enzyme of SEQ ID NO:22, wherein the mutant TET enzyme consists of a T248S amino acid substitution (identified as “T1372S” in the specification or hTET-CD-T1372S).
The elected species is free of the prior art. Therefore, search and examination has been extended to all subsequent species and the election of species requirement of the Office Action mailed on July 19, 2024 has been withdrawn.
Status of Claims
Claims 10-11, 13, 15-22, 24-25, 27-28, and 31-32 are pending.
Claims 10-11, 13, 15-22, 24-25, 27-28, and 31-32 are under examination.
Response to Amendments/Arguments
Incorporation by Reference
Claims 13 and 28 have been amended to delete incorporation of a subject matter into the application, SEQ ID NO:151, 154, 153, and 156. Claims 29-30 have been cancelled. A new Sequence Listing was filed on November 6, 2025 that is identical to the Sequence Listing present in the original application.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Withdrawn Rejections
Applicant’s arguments, see page 7 of the Remarks, filed November 6, 2025, with respect to claim 13 have been fully considered and are persuasive. Claim 13 has been amended to delete recitation of “encoded by SEQ ID NO:151 or 154”. Therefore, the rejection of claim 13 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments, see page 7 of the Remarks, filed November 6, 2025, with respect to claim 27 have been fully considered and are persuasive. Claim 27 has been amended to recite “mutant TET2 enzyme of claim 10, encoded by SEQ ID NO:147” and no longer recites the indefinite limitations. Therefore, the rejections of claim 27 under 35 U.S.C. 112(b) have been withdrawn.
Applicant’s arguments, see page 7 of the Remarks, filed November 6, 2025, with respect to claim 28 have been fully considered and are persuasive. Claim 28 has been amended to delete SEQ ID NO:156 and 156 and no longer recites the indefinite limitations. Therefore, the rejections of claim 28 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments, see page 7 of the Remarks, filed November 6, 2025, with respect to claims 29-30 have been fully considered and are persuasive. Claims 29-30 have been cancelled. Therefore, the rejections of claims 29-30 under 35 U.S.C. 112(b) have been withdrawn.
Maintained Rejection
Claim 11 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 recites the limitation “mutant TET2 enzyme… encoded by the nucleic acid of SEQ ID NO:146”. The metes and bounds of the limitation in the context of the claim are not clear. It is unclear if the mutant TET2 enzyme is encoded by the nucleic acid sequence of SEQ ID NO:146, as in the full length of SEQ ID NO:146 or is encoded by one nucleic acid of SEQ ID NO:146. Clarification is requested.
Applicant's arguments filed November 6, 2025 have been fully considered but they are not persuasive.
At page 7, Applicant argues that the rejection is moot since claim 11 has been amended to include the term “sequence”.
This is not found persuasive. Claim 11 has not been amended to recite “encoded by the nucleic acid sequence of SEQ ID NO:146”. Therefore, the rejection has been maintained.
New Rejections
Claims 21-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 recites the limitation “the enzyme is SEQ ID NO:23” and claim 22 recite the limitation “the enzyme is SEQ ID NO:24”. The metes and bounds of the limitations in the context of the claim are not clear. It is unclear how an enzyme is “SEQ ID NO:23” or “SEQ ID NO:24”. Clarification is requested.
This rejection maybe overcome by reciting “the enzyme comprises the amino acid sequence of SEQ ID NO:23”, for example.
Claim 32 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 recites the limitation “SEQ ID NO:21 or 22, …(1) T248.. or T258.. .. respectively, (2) Y778F ..Y440F, and, or (3) T248A+Y778F.. or T258+440F.. respectively”. The metes and bounds of the limitations in the context of the claim are not clear. SEQ ID NO:21 does not have a T248 nor Y778F. SEQ ID NO:22 does not have a T258 nor Y440. Clarification is requested.
This rejection maybe overcome by reciting “SEQ ID NO:22 or 21, …(1) T248.. or T258.. .. respectively, (2) Y778F ..Y440F, respectively, and, or (3) T248A+Y778F.. or T258+440F.. respectively”, for example.
Claim Rejections - 35 USC § 112(d)
Applicant’s arguments, see page 8 of the Remarks, filed November 6, 2025, with respect to claim 30 have been fully considered and are persuasive. Claim 30 has been cancelled. Therefore, the rejection of claim 30 under 35 U.S.C. 112(d) have been withdrawn.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Withdrawn Rejection
Applicant’s arguments, see pages 9-10 of the Remarks, filed November 6, 2025, with respect to claims 13 and 28-30 have been fully considered and are persuasive. Claims 29-30 have been cancelled. Claims 13 and 28 have been amended to delete the new matter. Therefore, the rejection of claims 13 and 28-30 under 35 U.S.C. 112(a) has been withdrawn.
Maintained Rejection
Claims 10-11, 13, 15-20, 24-25, 28, and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' In this case, the phrase “an amino acid sequence” recited in claim 10 has been broadly interpreted as encompass any two contiguous amino acids of SEQ ID NO:21 or 22. The phrase “the nucleic acid of SEQ ID NO:146” recited in claim 11 has been broadly interpreted as any two contiguous nucleic acids of SEQ ID NO:146. Therefore, claims 10, 15-20, 24-25, and 31 encompass any mutant TET2 enzyme comprising as little as two contiguous amino acids of SEQ ID NO:21 or 22 having an amino acid substitution at the position corresponding to 258 or 248, respectively, and also having any other amino acid mutations, wherein the mutant TET2 enzyme has the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) when said threonine is substituted for glutamine, asparagine, aspartic acid, glutamic acid, or valine or accelerating production of 5-carboxycytosine by at least 20% as compared to wild type enzyme activity when said threonine is substituted with a serine. Claim 11 encompass any mutant TET2 enzyme encoded by as little as two contiguous nucleic acids of SEQ ID NO:146, wherein the mutant TET2 enzyme has an amino acid substitution at the position corresponding to 258 or 248 of SEQ ID NO: 21 or 22, respectively and also has any other amino acid mutations, wherein the mutant TET2 enzyme has the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) when said threonine is substituted for glutamine, asparagine, aspartic acid, glutamic acid, or valine or accelerating production of 5-carboxycytosine by at least 20% as compared to any wild type enzyme activity when said threonine is substituted with a serine. Claim 13 encompasses any mutant human TET1 enzyme comprising a catalytic domain comprising as little as two contiguous amino acids of SEQ ID NO:130 and having a mutation at the position corresponding to 6 and also having any other amino acid mutations, wherein said mutation alters stability activity or accelerates production of 5-caroxylcytosine as compared to any wildtype TET1 enzymes. Claim 28 encompass any mutant human TET3 enzyme comprising a catalytic domain comprising as little as two contiguous amino acids of SEQ ID NO:134 and having a mutation at the position corresponding to 6 and also having any other amino acid mutations, wherein said mutation alters stability activity or accelerates production of 5-carboxylcytosine as compared to any wildtype enzyme activity. Therefore, the claims are directed to (A) a genus of mutant TET2 enzymes having unknown structure but having the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) when said threonine is substituted for glutamine, asparagine, aspartic acid, glutamic acid, or valine or accelerating production of 5-carboxycytosine by at least 20% as compared to any wild type enzyme activity when said threonine is substituted with a serine or (B) genus of mutant human TET1 and human TET3 enzymes having unknown structure but having altered stability activity or accelerated production of 5-carboxycytosine compared to any wildtype TET1 or TET3.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The recitation of “stalls oxidation at a 5-hydroxymethylcytosine (hmc) when said threonine is substituted for glutamine, asparagine, aspartic acid or glutamic acid or accelerates production of 5-carboxycytosine by at least 20% as compared to wild type enzyme activity when said threonine is substituted with a serine” and “altering stalling activity or catalytic activity” compared to wild type TET1 or TET3 fails to provide a sufficient description of the genus of the mutant TET enzymes it merely describes the functional features of the genus without providing any definition of the structural features of the species within the genus. The specification does not specifically define any of the species that fall within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
Hu (Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell. 2013 Dec 19;155(7):1545-55. Epub 2013 Dec 5 - form PTO-1449) discloses the catalytic domain of human TET2 comprising of amino acids 1129-1936 of the full length human TET2 (Figure 1 and page 1546, left column and page 1554, 1st paragraph). This catalytic domain is identical to amino acids 5-878 of SEQ ID NO:22 of the instant application (see the sequence alignment below). Hu discloses double-stranded β helix (DSBH) core (pages 1546-1547). However, the prior art does not teach (A) TET2 mutants having any structure but having the having the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) when said threonine is substituted for glutamine, asparagine, aspartic acid, glutamic acid, or valine or accelerating production of 5-carboxycytosine by at least 20% as compared to any wild type enzyme activity when said threonine is substituted with a serine or (B) TET1 and TET3 mutants having any structure but having altered stalling activity or accelerates production of 5-carboxycytosine enzyme compared to any wildtype TET1 enzyme or any wildtype TET3 enzyme.
Fransceus (J Ind Microbiol Biotechnol. 2017 May;44(4-5):687-695. – cited previously on form PTO-892) reviews protein engineering techniques, such as random mutagenesis and recombination, directed evolution and iterative or combinatory saturation “hotspots”. Fransceus states that “a recurring problem, however, is choosing which amino acid positions should be targeted. Answering this question is not an easy feat and requires substantial insight in the relationship between an enzyme’s sequence or structure and its properties.” Sanavia (Computational and Structural Biotechnology Journal, Volume 18, 2020, Pages 1968-1979. – cited previously on form PTO-892) discloses challenges in the prediction of protein stability in the occurrence of multiple mutations. “Multiple-point mutations are common variations of the protein sequence that may be needed in protein engineering when a single-point mutation is not enough to yield the desired stability change. Dealing with multiple-site variations adds another level of complexity beyond the prediction of the effect of a single variant on protein stability, since it requires the learning of many types of combinatorial effects”.
SEQ ID NO:22 consists of MGGS + the entire catalytic domain of human TET2 and SEQ ID NO:21 is a variant of SEQ ID NO:22 having linkers removed. SEQ ID NO:130 is the amino acid sequence of the catalytic domain of human TET1 enzyme. SEQ ID NO:134 is the amino acid sequence of the catalytic domain of human TET3 enzyme. The specification is limited to the disclosure of a mutant human TET2 enzyme of SEQ ID NO:21 or 22, wherein the mutant TET2 enzyme consists of (1) T248S/Q/N/D/E amino acid substitution or T258S/Q/N/D/E amino acid substitution, respectively (corresponding to T1372S/Q/N/D/E of full length wildtype human TET2 enzyme), (2) Y778F amino acid substitution or Y440F amino acid substitution, respectively (corresponding to Y1902F of full length wildtype human TET2 enzyme), and (3) T248A+Y778F amino acid substitutions or T258A+Y440F amino acid substitutions, respectively (corresponding to T1372A + Y1902F of full length wildtype human TET2 enzyme), wherein the mutant TET2 enzyme has the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) or accelerating production of 5-carboxycytosine and have the function of having increased enzyme activity by at least 20% as compared to the corresponding human TET2 enzyme of SEQ ID NO:22 or 21. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the examples of two mutant TET2 enzymes described above is not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe a representative species of the claimed genus.
Further, one of skill in the art could identify variants of human TET1, TET2, and TET3 enzymes. However, there is no teaching regarding which amino acid other than at positions 258 and 440 of SEQ ID NO:21 and positions 248 and 778 of SEQ ID NO:22 result in a human TET2 enzyme having the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) or accelerating production of 5-carboxycytosine by at least 20% as compared to wild type enzyme activity or which amino acid other than at position 6 of SEQ ID NO:130 or 134 results in a human TET1 or humanTET3 enzyme having the function of having altered stalling activity or accelerating production of 5-carboxycytosine.
An important consideration is that structure is not necessarily a reliable indicator of function. In the instant case, there is no disclosure relating similarity of structure to conservation of function. Conservation of structure is not necessarily a surrogate for conservation of function. Since the claimed invention is that of an enzyme, and there is no disclosure of the domains responsible for having the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) or accelerating production of 5-carboxycytosine by at least 20% as compared to wild type enzyme activity or altered stalling activity or accelerating production of 5-carboxycytosine, the absence of information may be persuasive that those of skill in the art would not take the disclosure as generic.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 10-11, 13, 15-20, 24-25, 28, and 31.
As disclosed previously, an example of claim language that may overcome the above rejection is: “A mutant Ten-Eleven translocation 2 (TET2) enzyme comprising the amino acid sequence of SEQ ID NO:21 or 22 except having one or two mutations in a catalytic domain active site, wherein said mutation is a substitution of a threonine residue at position number 258 or 248, respectively, which i).. or ii)..”
Applicant's arguments filed November 6, 2025 have been fully considered but they are not persuasive.
Applicant argues that the amended claims cannot read on a single nucleic acid or a single amino acid.
This is not found persuasive. MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' In this case, the phrase “an amino acid sequence” recited in claim 10 has been broadly interpreted as encompass any two contiguous amino acids of SEQ ID NO:21 or 22. The phrase “the nucleic acid of SEQ ID NO:146” recited in claim 11 has been broadly interpreted as any two contiguous nucleic acids of SEQ ID NO:146.
Applicant argues that the person of skill in TET enzyme biology would fully appreciate that the present inventors were in possession of the claimed invention because (A) the biological function of TET1, TET2, and TET3 in converting 5mC to 5hmC and further to 5caC was known, (B) Figures 11A, 12, 13, and 17C show that TET1, TET2, and TET3 enzymes contain highly conserved carboxy-terminal catalytic domain and this domain possesses key residues which are necessary for its catalytic function, and (C) claim 10 has been amended in keeping with the Examiner’s suggestion at the bottom of page 19 of the Official Action (mailed on August 6, 2025).
This is not found persuasive. (C) Claim 10 has not been amended in keeping with the Examiner’s suggestion at the bottom of page 19 of the Official Action. (A)-(B) The claims are directed to a genus of mutant TET2 enzymes having unknown structure but having the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) when said threonine is substituted for glutamine, asparagine, aspartic acid glutamic acid, or valine or accelerating production of 5-carboxycytosine by at least 20% as compared to any wild type enzyme activity when said threonine is substituted with a serine or (B) genus of mutant human TET1 and human TET3 enzymes having unknown structure but having altered stalling activity or accelerated production of 5-carboxycytosine compared to any wildtype TET1 or TET3.
The specification is limited to the disclosure of a mutant humanTET2 enzyme of SEQ ID NO:22 or 21, wherein the mutant TET enzyme consists of (1) T248S/Q/N/D/E amino acid substitution or T258S/Q/N/D/E amino acid substitution, respectively (corresponding to T1372S/Q/N/D/E of full length wildtype human TET2 enzyme), (2) Y778F amino acid substitution or Y440F amino acid substitution, respectively (corresponding to Y1902F of full length wildtype human TET2 enzyme), and (3) T248A+Y778F amino acid substitutions or T258A+Y440F amino acid substitutions, respectively (corresponding to T1372A + Y1902F of full length wildtype human TET2 enzyme). One of skill in the art could identify variants of TET1, TET2, and TET3 enzymes. However, there is no teaching regarding which amino acid other than at positions 258 and 440 of SEQ ID NO:21 and positions 248 and 778 of SEQ ID NO:22 result in a TET2 enzyme having the function of stalling oxidation at a 5-hydroxymethylcytosine (hmc) or accelerating production of 5-carboxycytosine by at least 20% as compared to wild type enzyme activity or which amino acid other than at position 6 of SEQ ID NO:130 or 134 results in a TET1 or TET3 enzyme having the function of having altered stalling activity or accelerating production of 5-carboxycytosine.
Hence the rejection is maintained.
Conclusion
Claims 10-11, 13, 15-22, 24-25, 27-28, and 31-32 are pending.
Claims 10-11, 13, 15-22, 24-25, 28, and 31-32 are rejected.
Claims 27 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on 408-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YONG D PAK/Primary Examiner, Art Unit 1652
Sequence alignment between TET enzyme of SEQ ID NO:22 of the instant application (“Qy”) and human TET2 enzyme of Hu (“Db”)
TET2_HUMAN
ID TET2_HUMAN Reviewed; 2002 AA.
AC Q6N021; B5MDU0; Q2TB88; Q3LIB8; Q96JX5; Q9HCM6; Q9NXW0;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 16-JUN-2009, sequence version 3.
DT 24-JAN-2024, entry version 155.
DE RecName: Full=Methylcytosine dioxygenase TET2;
DE EC=1.14.11.80 {ECO:0000269|PubMed:24315485, ECO:0000269|PubMed:32518946};
GN Name=TET2; Synonyms=KIAA1546; ORFNames=Nbla00191;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT MET-218.
RC TISSUE=Fetal kidney;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 301-2002 (ISOFORM 2).
RC TISSUE=Adipose tissue, and Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 791-2002 (ISOFORM 3).
RC TISSUE=Neuroblastoma;
RX PubMed=12880961; DOI=10.1016/s0304-3835(03)00085-5;
RA Ohira M., Morohashi A., Nakamura Y., Isogai E., Furuya K., Hamano S.,
RA Machida T., Aoyama M., Fukumura M., Miyazaki K., Suzuki Y., Sugano S.,
RA Hirato J., Nakagawara A.;
RT "Neuroblastoma oligo-capping cDNA project: toward the understanding of the
RT genesis and biology of neuroblastoma.";
RL Cancer Lett. 197:63-68(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1198-2002 (ISOFORM 1), AND
RP VARIANT VAL-1762.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1319-2002 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10997877; DOI=10.1093/dnares/7.4.271;
RA Nagase T., Kikuno R., Nakayama M., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVIII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:273-281(2000).
RN [7]
RP IDENTIFICATION, AND TISSUE SPECIFICITY.
RX PubMed=12646957; DOI=10.1038/sj.leu.2402834;
RA Lorsbach R.B., Moore J., Mathew S., Raimondi S.C., Mukatira S.T.,
RA Downing J.R.;
RT "TET1, a member of a novel protein family, is fused to MLL in acute myeloid
RT leukemia containing the t(10;11)(q22;q23).";
RL Leukemia 17:637-641(2003).
RN [8]
RP IDENTIFICATION.
RX PubMed=15375572; DOI=10.3892/ijo.25.4.1193;
RA Katoh M., Katoh M.;
RT "Identification and characterization of human CXXC10 gene in silico.";
RL Int. J. Oncol. 25:1193-1199(2004).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP INTERACTION WITH DCAF1.
RX PubMed=24357321; DOI=10.1126/science.1244587;
RA Yu C., Zhang Y.L., Pan W.W., Li X.M., Wang Z.W., Ge Z.J., Zhou J.J.,
RA Cang Y., Tong C., Sun Q.Y., Fan H.Y.;
RT "CRL4 complex regulates mammalian oocyte survival and reprogramming by
RT activation of TET proteins.";
RL Science 342:1518-1521(2013).
RN [12]
RP INTERACTION WITH DCAF1, MONOUBIQITINATION AT LYS-1299, SUBCELLULAR
RP LOCATION, CHARACTERIZATION OF VARIANTS LEU-1287; ARG-1291; ASN-1299;
RP GLU-1299; GLY-1302 AND GLY-1318, AND MUTAGENESIS OF SER-1292; CYS-1298 AND
RP PHE-1300.
RX PubMed=25557551; DOI=10.1016/j.molcel.2014.12.002;
RA Nakagawa T., Lv L., Nakagawa M., Yu Y., Yu C., D'Alessio A.C., Nakayama K.,
RA Fan H.Y., Chen X., Xiong Y.;
RT "CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of
RT TET dioxygenases.";
RL Mol. Cell 57:247-260(2015).
RN [13]
RP INVOLVEMENT IN MYELOID MALIGNANCIES, AND VARIANTS PHE-34; ASN-145; HIS-174;
RP SER-312; PHE-460; GLY-666; HIS-867; SER-941; VAL-1073; PRO-1084; TYR-1135;
RP CYS-1204; TRP-1214; VAL-1242; SER-1245; CYS-1261; HIS-1261; PHE-1417;
RP LEU-1718; SER-1723; ASP-1757; ARG-1811; LEU-1828; THR-1873; ARG-1881;
RP ALA-1900; VAL-1919; HIS-1926; SER-1941; HIS-1966; MET-1974 AND LYS-2000.
RX PubMed=19420352; DOI=10.1182/blood-2009-03-210039;
RA Abdel-Wahab O., Mullally A., Hedvat C., Garcia-Manero G., Patel J.,
RA Wadleigh M., Malinge S., Yao J., Kilpivaara O., Bhat R., Huberman K.,
RA Thomas S., Dolgalev I., Heguy A., Paietta E., Le Beau M.M., Beran M.,
RA Tallman M.S., Ebert B.L., Kantarjian H.M., Stone R.M., Gilliland D.G.,
RA Crispino J.D., Levine R.L.;
RT "Genetic characterization of TET1, TET2, and TET3 alterations in myeloid
RT malignancies.";
RL Blood 114:144-147(2009).
RN [14]
RP INVOLVEMENT IN MDS, INVOLVEMENT IN MYELOPROLIFERATIVE DISORDERS, AND
RP VARIANTS THR-308; LEU-399; THR-817; HIS-867; PRO-1084; THR-1167; LEU-1287;
RP ASN-1299; GLY-1302; GLY-1318; LEU-1718; THR-1873 AND ASP-1913.
RX PubMed=19372255; DOI=10.1182/blood-2009-02-205690;
RA Jankowska A.M., Szpurka H., Tiu R.V., Makishima H., Afable M., Huh J.,
RA O'Keefe C.L., Ganetzky R., McDevitt M.A., Maciejewski J.P.;
RT "Loss of heterozygosity 4q24 and TET2 mutations associated with
RT myelodysplastic/myeloproliferative neoplasms.";
RL Blood 113:6403-6410(2009).
RN [15]
RP INVOLVEMENT IN SYSTEMIC MASTOCYTOSIS, AND VARIANT ARG-1881.
RX PubMed=19262599; DOI=10.1038/leu.2009.37;
RA Tefferi A., Levine R.L., Lim K.H., Abdel-Wahab O., Lasho T.L., Patel J.,
RA Finke C.M., Mullally A., Li C.Y., Pardanani A., Gilliland D.G.;
RT "Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and
RT FIP1L1-PDGFRA correlates.";
RL Leukemia 23:900-904(2009).
RN [16]
RP INVOLVEMENT IN MYELOPROLIFERATIVE DISORDERS, AND VARIANTS ARG-1242 AND
RP THR-1873.
RX PubMed=19262601; DOI=10.1038/leu.2009.47;
RA Tefferi A., Pardanani A., Lim K.H., Abdel-Wahab O., Lasho T.L., Patel J.,
RA Gangat N., Finke C.M., Schwager S., Mullally A., Li C.-Y., Hanson C.A.,
RA Mesa R., Bernard O., Delhommeau F., Vainchenker W., Gilliland D.G.,
RA Levine R.L.;
RT "TET2 mutations and their clinical correlates in polycythemia vera,
RT essential thrombocythemia and myelofibrosis.";
RL Leukemia 23:905-911(2009).
RN [17]
RP INVOLVEMENT IN MDS, FUNCTION, TISSUE SPECIFICITY, AND VARIANTS ARG-29;
RP PHE-34; HIS-123; MET-218; ASP-355; LEU-363; ARG-429; HIS-867; ARG-924;
RP ARG-949; PRO-1084; TRP-1214; LEU-1261; PHE-1285 DEL; ARG-1291; TRP-1396;
RP ARG-1398; ILE-1701; TRP-1721; SER-1723; VAL-1762; ARG-1778; THR-1873;
RP ARG-1875; GLN-1881; SER-1896; 1911-LYS--LEU-1916 DEL; ASP-1913 AND
RP LEU-1962.
RX PubMed=19483684; DOI=10.1038/ng.391;
RA Langemeijer S.M.C., Kuiper R.P., Berends M., Knops R., Aslanyan M.G.,
RA Massop M., Stevens-Linders E., van Hoogen P., van Kessel A.G.,
RA Raymakers R.A.P., Kamping E.J., Verhoef G.E., Verburgh E., Hagemeijer A.,
RA Vandenberghe P., de Witte T., van der Reijden B.A., Jansen J.H.;
RT "Acquired mutations in TET2 are common in myelodysplastic syndromes.";
RL Nat. Genet. 41:838-842(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99 AND SER-1107, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [19]
RP FUNCTION, INVOLVEMENT IN MDS, AND INVOLVEMENT IN MYELOPROLIFERATIVE
RP DISORDERS.
RX PubMed=21057493; DOI=10.1038/nature09586;
RA Ko M., Huang Y., Jankowska A.M., Pape U.J., Tahiliani M., Bandukwala H.S.,
RA An J., Lamperti E.D., Koh K.P., Ganetzky R., Liu X.S., Aravind L.,
RA Agarwal S., Maciejewski J.P., Rao A.;
RT "Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant
RT TET2.";
RL Nature 468:839-843(2010).
RN [20]
RP FUNCTION.
RX PubMed=21817016; DOI=10.1126/science.1210944;
RA He Y.F., Li B.Z., Li Z., Liu P., Wang Y., Tang Q., Ding J., Jia Y.,
RA Chen Z., Li L., Sun Y., Li X., Dai Q., Song C.X., Zhang K., He C., Xu G.L.;
RT "Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in
RT mammalian DNA.";
RL Science 333:1303-1307(2011).
RN [21]
RP FUNCTION, AND INTERACTION WITH HCFC1 AND OGT.
RX PubMed=23353889; DOI=10.1038/emboj.2012.357;
RA Deplus R., Delatte B., Schwinn M.K., Defrance M., Mendez J., Murphy N.,
RA Dawson M.A., Volkmar M., Putmans P., Calonne E., Shih A.H., Levine R.L.,
RA Bernard O., Mercher T., Solary E., Urh M., Daniels D.L., Fuks F.;
RT "TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and
RT SET1/COMPASS.";
RL EMBO J. 32:645-655(2013).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-75; SER-99; SER-1107 AND
RP SER-1109, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [23]
RP FUNCTION, INTERACTION WITH OGT, AND MUTAGENESIS OF HIS-1382 AND ASP-1384.
RX PubMed=23222540; DOI=10.1038/nature11742;
RA Chen Q., Chen Y., Bian C., Fujiki R., Yu X.;
RT "TET2 promotes histone O-GlcNAcylation during gene transcription.";
RL Nature 493:561-564(2013).
RN [24]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-1682, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Colon carcinoma;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [25]
RP INTERACTION WITH PROSER1.
RX PubMed=34667079; DOI=10.26508/lsa.202101228;
RA Wang X., Rosikiewicz W., Sedkov Y., Martinez T., Hansen B.S., Schreiner P.,
RA Christensen J., Xu B., Pruett-Miller S.M., Helin K., Herz H.M.;
RT "PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on
RT UTX-dependent enhancers and CpG islands.";
RL Life. Sci Alliance 5:0-0(2022).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) OF 1129-1480 AND 1844-1936 IN
RP COMPLEX WITH DNA; IRON; N-OXALYOLGLYCINE AND ZINC, CATALYTIC ACTIVITY,
RP FUNCTION, CHARACTERIZATION OF VARIANTS ARG-1291; GLU-1299; MET-1896 AND
RP PHE-1898, AND MUTAGENESIS OF ARG-1261; ARG-1262; SER-1290;
RP 1291-TRP--ASN-1296; 1293-MET-TYR-1294; TYR-1295; SER-1303; HIS-1382;
RP ASP-1384; ASN-1387; TYR-1902 AND HIS-1904.
RX PubMed=24315485; DOI=10.1016/j.cell.2013.11.020;
RA Hu L., Li Z., Cheng J., Rao Q., Gong W., Liu M., Shi Y.G., Zhu J., Wang P.,
RA Xu Y.;
RT "Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC
RT oxidation.";
RL Cell 155:1545-1555(2013).
RN [27]
RP VARIANTS VAL-1175; 1237-PRO--SER-1239 DEL; GLU-1299; GLY-1302; TRP-1869;
RP PRO-1872; THR-1873; MET-1896 AND PHE-1898.
RX PubMed=19474426; DOI=10.1056/nejmoa0810069;
RA Delhommeau F., Dupont S., Della Valle V., James C., Trannoy S., Masse A.,
RA Kosmider O., Le Couedic J.-P., Robert F., Alberdi A., Lecluse Y., Plo I.,
RA Dreyfus F.J., Marzac C., Casadevall N., Lacombe C., Romana S.P., Dessen P.,
RA Soulier J., Viguie F., Fontenay M., Vainchenker W., Bernard O.A.;
RT "Mutation in TET2 in myeloid cancers.";
RL N. Engl. J. Med. 360:2289-2301(2009).
RN [28]
RP INVOLVEMENT IN IMD75, VARIANTS IMD75 ARG-1382 AND 1632-GLN--ILE-2002 DEL,
RP CHARACTERIZATION OF VARIANTS IMD75 ARG-1382 AND 1632-GLN--ILE-2002 DEL,
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=32518946; DOI=10.1182/blood.2020005844;
RA Stremenova Spegarova J., Lawless D., Mohamad S.M.B., Engelhardt K.R.,
RA Doody G., Shrimpton J., Rensing-Ehl A., Ehl S., Rieux-Laucat F., Cargo C.,
RA Griffin H., Mikulasova A., Acres M., Morgan N.V., Poulter J.A.,
RA Sheridan E.G., Chetcuti P., O'Riordan S., Anwar R., Carter C.R.,
RA Przyborski S., Windebank K., Cant A.J., Lako M., Bacon C.M., Savic S.,
RA Hambleton S.;
RT "Germline TET2 loss of function causes childhood immunodeficiency and
RT lymphoma.";
RL Blood 136:1055-1066(2020).
CC -!- FUNCTION: Dioxygenase that catalyzes the conversion of the modified
CC genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC)
CC and plays a key role in active DNA demethylation. Has a preference for
CC 5-hydroxymethylcytosine in CpG motifs. Also mediates subsequent
CC conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC
CC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC
CC probably constitutes the first step in cytosine demethylation.
CC Methylation at the C5 position of cytosine bases is an epigenetic
CC modification of the mammalian genome which plays an important role in
CC transcriptional regulation. In addition to its role in DNA
CC demethylation, also involved in the recruitment of the O-GlcNAc
CC transferase OGT to CpG-rich transcription start sites of active genes,
CC thereby promoting histone H2B GlcNAcylation by OGT.
CC {ECO:0000269|PubMed:19483684, ECO:0000269|PubMed:21057493,
CC ECO:0000269|PubMed:21817016, ECO:0000269|PubMed:23222540,
CC ECO:0000269|PubMed:23353889, ECO:0000269|PubMed:24315485,
CC ECO:0000269|PubMed:32518946}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + a 5-methyl-2'-deoxycytidine in DNA + O2 = a
CC 5-hydroxymethyl-2'-deoxycytidine in DNA + CO2 + succinate;
CC Xref=Rhea:RHEA:52636, Rhea:RHEA-COMP:11370, Rhea:RHEA-COMP:13315,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810,
CC ChEBI:CHEBI:30031, ChEBI:CHEBI:85454, ChEBI:CHEBI:136731;
CC EC=1.14.11.80; Evidence={ECO:0000269|PubMed:24315485,
CC ECO:0000269|PubMed:32518946};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52637;
CC Evidence={ECO:0000269|PubMed:32518946};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + a 5-hydroxymethyl-2'-deoxycytidine in DNA +
CC O2 = a 5-formyl-2'-deoxycytidine in DNA + CO2 + H2O + succinate;
CC Xref=Rhea:RHEA:53828, Rhea:RHEA-COMP:13315, Rhea:RHEA-COMP:13656,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:30031, ChEBI:CHEBI:136731,
CC ChEBI:CHEBI:137731; EC=1.14.11.80;
CC Evidence={ECO:0000269|PubMed:24315485};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + a 5-formyl-2'-deoxycytidine in DNA + O2 = a
CC 5-carboxyl-2'-deoxycytidine in DNA + CO2 + H(+) + succinate;
CC Xref=Rhea:RHEA:53832, Rhea:RHEA-COMP:13656, Rhea:RHEA-COMP:13657,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:30031, ChEBI:CHEBI:137731,
CC ChEBI:CHEBI:137732; EC=1.14.11.80;
CC Evidence={ECO:0000269|PubMed:24315485};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000269|PubMed:24315485};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:24315485};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:24315485};
CC Note=Binds 3 zinc ions per subunit. The zinc ions have a structural
CC role (PubMed:24315485). {ECO:0000269|PubMed:24315485};
CC -!- SUBUNIT: Interacts with HCFC1 (PubMed:23353889). Interacts with OGT
CC (PubMed:23353889, PubMed:23222540). Interacts with PROSER1; this
CC interaction mediates TET2 O-GlcNAcylation and stability by promoting
CC the interaction between OGT and TET2 (PubMed:34667079). Directly
CC interacts (via C-terminus) with the DCAF1 component of the CRL4(VprBP)
CC E3 ubiquitin-protein ligase complex (PubMed:24357321, PubMed:25557551).
CC {ECO:0000269|PubMed:23222540, ECO:0000269|PubMed:23353889,
CC ECO:0000269|PubMed:24315485, ECO:0000269|PubMed:24357321,
CC ECO:0000269|PubMed:25557551, ECO:0000269|PubMed:34667079}.
CC -!- INTERACTION:
CC Q6N021; P22607: FGFR3; NbExp=3; IntAct=EBI-310727, EBI-348399;
CC Q6N021; P06396: GSN; NbExp=3; IntAct=EBI-310727, EBI-351506;
CC Q6N021; O15294: OGT; NbExp=7; IntAct=EBI-310727, EBI-539828;
CC Q6N021; P29590: PML; NbExp=2; IntAct=EBI-310727, EBI-295890;
CC Q6N021; P19544: WT1; NbExp=9; IntAct=EBI-310727, EBI-2320534;
CC Q6N021-1; O15294: OGT; NbExp=5; IntAct=EBI-20717492, EBI-539828;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:25557551}. Chromosome
CC {ECO:0000269|PubMed:25557551}. Note=Localization to chromatin depends
CC upon monoubiquitination at Lys-1299. {ECO:0000269|PubMed:25557551}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q6N021-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6N021-2; Sequence=VSP_032283, VSP_032284;
CC Name=3;
CC IsoId=Q6N021-3; Sequence=VSP_032282, VSP_032285;
CC -!- TISSUE SPECIFICITY: Broadly expressed. Highly expressed in
CC hematopoietic cells; highest expression observed in granulocytes.
CC Expression is reduced in granulocytes from peripheral blood of patients
CC affected by myelodysplastic syndromes. {ECO:0000269|PubMed:12646957,
CC ECO:0000269|PubMed:19483684}.
CC -!- PTM: May be glycosylated. It is unclear whether interaction with OGT
CC leads to GlcNAcylation. According to a report, it is not GlcNAcylated
CC by OGT (PubMed:23353889). In contrast, another group reports
CC GlcNAcylation by OGT in mouse ortholog. {ECO:0000269|PubMed:23353889}.
CC -!- PTM: Monoubiquitinated at Lys-1299 by the DCX (DDB1-CUL4-X-box) E3
CC ubiquitin-protein ligase complex called CRL4(VprBP) or CUL4A-RBX1-DDB1-
CC DCAF1/VPRBP complex; this modification promotes binding to DNA.
CC {ECO:0000269|PubMed:25557551}.
CC -!- DISEASE: Note=TET2 is frequently mutated in myeloproliferative
CC disorders (MPD). These constitute a heterogeneous group of disorders,
CC also known as myeloproliferative diseases or myeloproliferative
CC neoplasms (MPN), characterized by cellular proliferation of one or more
CC hematologic cell lines in the peripheral blood, distinct from acute
CC leukemia. Included diseases are: essential thrombocythemia,
CC polycythemia vera, primary myelofibrosis (chronic idiopathic
CC myelofibrosis). Bone marrow samples from patients display uniformly low
CC levels of hmC in genomic DNA compared to bone marrow samples from
CC healthy controls as well as hypomethylation relative to controls at the
CC majority of differentially methylated CpG sites.
CC -!- DISEASE: Polycythemia vera (PV) [MIM:263300]: A myeloproliferative
CC disorder characterized by abnormal proliferation of all hematopoietic
CC bone marrow elements, erythroid hyperplasia, an absolute increase in
CC total blood volume, but also by myeloid leukocytosis, thrombocytosis
CC and splenomegaly. Note=The disease is caused by variants affecting the
CC gene represented in this entry.
CC -!- DISEASE: Note=TET2 is frequently mutated in systemic mastocytosis; also
CC known as systemic mast cell disease. A condition with features in
CC common with myeloproliferative diseases. It is a clonal disorder of the
CC mast cell and its precursor cells. The clinical symptoms and signs of
CC systemic mastocytosis are due to accumulation of clonally derived mast
CC cells in different tissues, including bone marrow, skin, the
CC gastrointestinal tract, the liver, and the spleen.
CC -!- DISEASE: Myelodysplastic syndrome (MDS) [MIM:614286]: A heterogeneous
CC group of closely related clonal hematopoietic disorders. All are
CC characterized by a hypercellular or hypocellular bone marrow with
CC impaired morphology and maturation, dysplasia of the myeloid,
CC megakaryocytic and/or erythroid lineages, and peripheral blood
CC cytopenias resulting from ineffective blood cell production. Included
CC diseases are: refractory anemia (RA), refractory anemia with ringed
CC sideroblasts (RARS), refractory anemia with excess blasts (RAEB),
CC refractory cytopenia with multilineage dysplasia and ringed
CC sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a
CC myelodysplastic/myeloproliferative disease. MDS is considered a
CC premalignant condition in a subgroup of patients that often progresses
CC to acute myeloid leukemia (AML). {ECO:0000269|PubMed:19372255,
CC ECO:0000269|PubMed:19483684, ECO:0000269|PubMed:21057493}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Bone marrow samples from patients display uniformly low levels
CC of hmC in genomic DNA compared to bone marrow samples from healthy
CC controls as well as hypomethylation relative to controls at the
CC majority of differentially methylated CpG sites.
CC -!- DISEASE: Immunodeficiency 75 with lymphoproliferation (IMD75)
CC [MIM:619126]: An autosomal recessive immunologic disorder characterized
CC by recurrent infections, mainly viral and affecting the respiratory
CC tract, immunodeficieny, immune dysregulation, and the development of
CC lymphoproliferative disorders, including lymphoma.
CC {ECO:0000269|PubMed:32518946}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the TET family. {ECO:0000305}.
CC -!- CAUTION: Subsequent steps in cytosine demethylation are subject to
CC discussion. According to a first model cytosine demethylation occurs
CC through deamination of 5hmC into 5-hydroxymethyluracil (5hmU) and
CC subsequent replacement by unmethylated cytosine by the base excision
CC repair system. According to another model, cytosine demethylation is
CC rather mediated via conversion of 5hmC into 5fC and 5caC, followed by
CC excision by TDG (PubMed:21817016). {ECO:0000305|PubMed:21817016}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA90898.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA90898.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAA90898.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC Sequence=BAB55391.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; BX640738; CAE45851.1; -; mRNA.
DR EMBL; AC004069; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC026029; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK000039; BAA90898.1; ALT_SEQ; mRNA.
DR EMBL; AK027819; BAB55391.1; ALT_INIT; mRNA.
DR EMBL; AB075496; BAE45750.1; -; mRNA.
DR EMBL; BC110509; AAI10510.1; -; mRNA.
DR EMBL; BC110510; AAI10511.2; -; mRNA.
DR EMBL; AB046766; BAB13372.1; -; mRNA.
DR CCDS; CCDS3666.1; -. [Q6N021-2]
DR CCDS; CCDS47120.1; -. [Q6N021-1]
DR RefSeq; NP_001120680.1; NM_001127208.2. [Q6N021-1]
DR RefSeq; NP_060098.3; NM_017628.4. [Q6N021-2]
DR RefSeq; XP_005263139.1; XM_005263082.2. [Q6N021-1]
DR PDB; 4NM6; X-ray; 2.03 A; A=1129-1480, A=1844-1936.
DR PDB; 5D9Y; X-ray; 1.97 A; A=1129-1480, A=1844-1936.
DR PDB; 5DEU; X-ray; 1.80 A; A=1129-1480, A=1844-1935.
DR PDB; 7NE3; X-ray; 2.26 A; A=1129-1480.
DR PDB; 7NE6; X-ray; 2.30 A; A=1129-1480.
DR PDBsum; 4NM6; -.
DR PDBsum; 5D9Y; -.
DR PDBsum; 5DEU; -.
DR PDBsum; 7NE3; -.
DR PDBsum; 7NE6; -.
DR AlphaFoldDB; Q6N021; -.
DR SMR; Q6N021; -.
DR BioGRID; 120151; 127.
DR IntAct; Q6N021; 34.
DR MINT; Q6N021; -.
DR STRING; 9606.ENSP00000442788; -.
DR BindingDB; Q6N021; -.
DR ChEMBL; CHEMBL4523344; -.
DR GlyGen; Q6N021; 9 sites, 1 O-linked glycan (9 sites).
DR iPTMnet; Q6N021; -.
DR PhosphoSitePlus; Q6N021; -.
DR BioMuta; TET2; -.
DR DMDM; 239938839; -.
DR EPD; Q6N021; -.
DR jPOST; Q6N021; -.
DR MassIVE; Q6N021; -.
DR MaxQB; Q6N021; -.
DR PaxDb; 9606-ENSP00000442788; -.
DR PeptideAtlas; Q6N021; -.
DR ProteomicsDB; 66598; -. [Q6N021-1]
DR ProteomicsDB; 66599; -. [Q6N021-2]
DR ProteomicsDB; 66600; -. [Q6N021-3]
DR Pumba; Q6N021; -.
DR Antibodypedia; 45118; 514 antibodies from 38 providers.
DR DNASU; 54790; -.
DR Ensembl; ENST00000265149.9; ENSP00000265149.5; ENSG00000168769.14. [Q6N021-3]
DR Ensembl; ENST00000305737.6; ENSP00000306705.2; ENSG00000168769.14. [Q6N021-2]
DR Ensembl; ENST00000380013.9; ENSP00000369351.4; ENSG00000168769.14. [Q6N021-1]
DR Ensembl; ENST00000540549.5; ENSP00000442788.1; ENSG00000168769.14. [Q6N021-1]
DR GeneID; 54790; -.
DR KEGG; hsa:54790; -.
DR MANE-Select; ENST00000380013.9; ENSP00000369351.4; NM_001127208.3; NP_001120680.1.
DR UCSC; uc003hxj.3; human. [Q6N021-1]
DR AGR; HGNC:25941; -.
DR CTD; 54790; -.
DR DisGeNET; 54790; -.
DR GeneCards; TET2; -.
DR HGNC; HGNC:25941; TET2.
DR HPA; ENSG00000168769; Tissue enhanced (bone).
DR MalaCards; TET2; -.
DR MIM; 263300; phenotype.
DR MIM; 612839; gene.
DR MIM; 614286; phenotype.
DR MIM; 619126; phenotype.
DR neXtProt; NX_Q6N021; -.
DR OpenTargets; ENSG00000168769; -.
DR Orphanet; 75564; Acquired idiopathic sideroblastic anemia.
DR Orphanet; 86845; Acute myeloid leukaemia with myelodysplasia-related features.
DR Orphanet; 98850; Aggressive systemic mastocytosis.
DR Orphanet; 3318; Essential thrombocythemia.
DR Orphanet; 729; Polycythemia vera.
DR Orphanet; 824; Primary myelofibrosis.
DR Orphanet; 98826; Refractory anemia.
DR Orphanet; 100019; Refractory anemia with excess blasts type 1.
DR Orphanet; 100020; Refractory anemia with excess blasts type 2.
DR Orphanet; 98849; Systemic mastocytosis with associated hematologic neoplasm.
DR PharmGKB; PA162405634; -.
DR VEuPathDB; HostDB:ENSG00000168769; -.
DR eggNOG; ENOG502QURD; Eukaryota.
DR GeneTree; ENSGT00940000160003; -.
DR HOGENOM; CLU_274735_0_0_1; -.
DR InParanoid; Q6N021; -.
DR OMA; HYSKPAW; -.
DR OrthoDB; 5406604at2759; -.
DR PhylomeDB; Q6N021; -.
DR TreeFam; TF337563; -.
DR PathwayCommons; Q6N021; -.
DR Reactome; R-HSA-5221030; TET1,2,3 and TDG demethylate DNA.
DR Reactome; R-HSA-9827857; Specification of primordial germ cells.
DR SignaLink; Q6N021; -.
DR SIGNOR; Q6N021; -.
DR BioGRID-ORCS; 54790; 8 hits in 1185 CRISPR screens.
DR ChiTaRS; TET2; human.
DR GenomeRNAi; 54790; -.
DR Pharos; Q6N021; Tchem.
DR PRO; PR:Q6N021; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q6N021; Protein.
DR Bgee; ENSG00000168769; Expressed in palpebral conjunctiva and 184 other cell types or tissues.
DR ExpressionAtlas; Q6N021; baseline and differential.
DR Genevisible; Q6N021; HS.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
DR GO; GO:0070579; F:methylcytosine dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0006211; P:5-methylcytosine catabolic process; IDA:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0080111; P:DNA demethylation; IDA:UniProtKB.
DR GO; GO:0002521; P:leukocyte differentiation; IMP:UniProtKB.
DR GO; GO:0030099; P:myeloid cell differentiation; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:UniProtKB.
DR GO; GO:0006493; P:protein O-linked glycosylation; IDA:UniProtKB.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR CDD; cd18896; TET2; 1.
DR InterPro; IPR024779; 2OGFeDO_JBP1/TET_oxygenase_dom.
DR InterPro; IPR040175; TET1/2/3.
DR InterPro; IPR046942; TET_oxygenase.
DR PANTHER; PTHR23358:SF3; METHYLCYTOSINE DIOXYGENASE TET2; 1.
DR PANTHER; PTHR23358; UNCHARACTERIZED; 1.
DR Pfam; PF12851; Tet_JBP; 1.
DR SMART; SM01333; Tet_JBP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell cycle; Chromatin regulator;
KW Chromosome; Dioxygenase; Disease variant; DNA-binding; Glycoprotein; Iron;
KW Isopeptide bond; Metal-binding; Methylation; Nucleus; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Tumor suppressor; Ubl conjugation;
KW Zinc.
FT CHAIN 1..2002
FT /note="Methylcytosine dioxygenase TET2"
FT /id="PRO_0000324588"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 113..154
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 266..287
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 349..368
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 390..488
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 703..748
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 930..949
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1075..1095
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1290..1303
FT /note="Interaction with DNA"
FT REGION 1475..1507
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1521..1587
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1932..1961
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
Query Match 99.6%; Score 4667; Length 2002;
Best Local Similarity 100.0%;
Matches 874; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 5 DFPSCRCVEQIIEKDEGPFYTHLGAGPNVAAIREIMEERFGQKGKAIRIERVIYTGKEGK 64
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1129 DFPSCRCVEQIIEKDEGPFYTHLGAGPNVAAIREIMEERFGQKGKAIRIERVIYTGKEGK 1188
Qy 65 SSQGCPIAKWVVRRSSSEEKLLCLVRERAGHTCEAAVIVILILVWEGIPLSLADKLYSEL 124
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1189 SSQGCPIAKWVVRRSSSEEKLLCLVRERAGHTCEAAVIVILILVWEGIPLSLADKLYSEL 1248
Qy 125 TETLRKYGTLTNRRCALNEERTCACQGLDPETCGASFSFGCSWSMYYNGCKFARSKIPRK 184
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1249 TETLRKYGTLTNRRCALNEERTCACQGLDPETCGASFSFGCSWSMYYNGCKFARSKIPRK 1308
Qy 185 FKLLGDDPKEEEKLESHLQNLSTLMAPTYKKLAPDAYNNQIEYEHRAPECRLGLKEGRPF 244
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1309 FKLLGDDPKEEEKLESHLQNLSTLMAPTYKKLAPDAYNNQIEYEHRAPECRLGLKEGRPF 1368
Qy 245 SGVTACLDFCAHAHRDLHNMQNGSTLVCTLTREDNREFGGKPEDEQLHVLPLYKVSDVDE 304
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1369 SGVTACLDFCAHAHRDLHNMQNGSTLVCTLTREDNREFGGKPEDEQLHVLPLYKVSDVDE 1428
Qy 305 FGSVEAQEEKKRSGAIQVLSSFRRKVRMLAEPVKTCRQRKLEAKKAAAEKLSSLENSSNK 364
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1429 FGSVEAQEEKKRSGAIQVLSSFRRKVRMLAEPVKTCRQRKLEAKKAAAEKLSSLENSSNK 1488
Qy 365 NEKEKSAPSRTKQTENASQAKQLAELLRLSGPVMQQSQQPQPLQKQPPQPQQQQRPQQQQ 424
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1489 NEKEKSAPSRTKQTENASQAKQLAELLRLSGPVMQQSQQPQPLQKQPPQPQQQQRPQQQQ 1548
Qy 425 PHHPQTESVNSYSASGSTNPYMRRPNPVSPYPNSSHTSDIYGSTSPMNFYSTSSQAAGSY 484
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1549 PHHPQTESVNSYSASGSTNPYMRRPNPVSPYPNSSHTSDIYGSTSPMNFYSTSSQAAGSY 1608
Qy 485 LNSSNPMNPYPGLLNQNTQYPSYQCNGNLSVDNCSPYLGSYSPQSQPMDLYRYPSQDPLS 544
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1609 LNSSNPMNPYPGLLNQNTQYPSYQCNGNLSVDNCSPYLGSYSPQSQPMDLYRYPSQDPLS 1668
Qy 545 KLSLPPIHTLYQPRFGNSQSFTSKYLGYGNQNMQGDGFSSCTIRPNVHHVGKLPPYPTHE 604
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1669 KLSLPPIHTLYQPRFGNSQSFTSKYLGYGNQNMQGDGFSSCTIRPNVHHVGKLPPYPTHE 1728
Qy 605 MDGHFMGATSRLPPNLSNPNMDYKNGEHHSPSHIIHNYSAAPGMFNSSLHALHLQNKEND 664
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1729 MDGHFMGATSRLPPNLSNPNMDYKNGEHHSPSHIIHNYSAAPGMFNSSLHALHLQNKEND 1788
Qy 665 MLSHTANGLSKMLPALNHDRTACVQGGLHKLSDANGQEKQPLALVQGVASGAEDNDEVWS 724
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1789 MLSHTANGLSKMLPALNHDRTACVQGGLHKLSDANGQEKQPLALVQGVASGAEDNDEVWS 1848
Qy 725 DSEQSFLDPDIGGVAVAPTHGSILIECAKRELHATTPLKNPNRNHPTRISLVFYQHKSMN 784
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1849 DSEQSFLDPDIGGVAVAPTHGSILIECAKRELHATTPLKNPNRNHPTRISLVFYQHKSMN 1908
Qy 785 EPKHGLALWEAKMAEKAREKEEECEKYGPDYVPQKSHGKKVKREPAEPHETSEPTYLRFI 844
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1909 EPKHGLALWEAKMAEKAREKEEECEKYGPDYVPQKSHGKKVKREPAEPHETSEPTYLRFI 1968
Qy 845 KSLAERTMSVTTDSTVTTSPYAFTRVTGPYNRYI 878
||||||||||||||||||||||||||||||||||
Db 1969 KSLAERTMSVTTDSTVTTSPYAFTRVTGPYNRYI 2002
PNG
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900
1186
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Greyscale