5exh

Crystal structure of mTET3-CXXC domain in complex with 5-carboxylcytosine DNA at 1.3 Angstroms resolution.Crystal structure of mTET3-CXXC domain in complex with 5-carboxylcytosine DNA at 1.3 Angstroms resolution.

Structural highlights

5exh is a 3 chain structure with sequence from Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TET3_MOUSE Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Selectively binds to the promoter region of target genes and contributes to regulate the expression of numerous developmental genes. In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Participates in DNA demethylation in the paternal pronucleus by mediating conversion of 5mC into 5hmC, 5fC and 5caC. Does not mediate DNA demethylation of maternal pronucleus because of the presence of DPPA3/PGC7 on maternal chromatin that prevents TET3-binding to chromatin. In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG (By similarity).[UniProtKB:O43151]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

We report that the mammalian 5-methylcytosine (5mC) oxidase Tet3 exists as three major isoforms and characterized the full-length isoform containing an N-terminal CXXC domain (Tet3FL). This CXXC domain binds to unmethylated CpGs, but, unexpectedly, its highest affinity is toward 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain-5caC-DNA complex, revealing the structural basis of the binding specificity of this domain as a reader of CcaCG sequences. Mapping of Tet3FL in neuronal cells shows that Tet3FL is localized precisely at the transcription start sites (TSSs) of genes involved in lysosome function, mRNA processing, and key genes of the base excision repair pathway. Therefore, Tet3FL may function as a regulator of 5caC removal by base excision repair. Active removal of accumulating 5mC from the TSSs of genes coding for lysosomal proteins by Tet3FL in postmitotic neurons of the brain may be important for preventing neurodegenerative diseases.

Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration.,Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabo PE, Lu Q, Xu GL, Song J, Pfeifer GP Cell Rep. 2016 Jan 26;14(3):493-505. doi: 10.1016/j.celrep.2015.12.044. Epub 2016, Jan 7. PMID:26774490^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010 Aug 26;466(7310):1129-33. PMID:20639862 doi:10.1038/nature09303
↑ Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun. 2011;2:241. doi: 10.1038/ncomms1240. PMID:21407207 doi:http://dx.doi.org/10.1038/ncomms1240
↑ Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011 Sep 2;333(6047):1300-3. doi: 10.1126/science.1210597. Epub 2011 Jul, 21. PMID:21778364 doi:http://dx.doi.org/10.1126/science.1210597
↑ Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabó PE, Pfeifer GP, Li J, Xu GL. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011 Sep 4;477(7366):606-10. PMID:21892189 doi:10.1038/nature10443
↑ Nakamura T, Liu YJ, Nakashima H, Umehara H, Inoue K, Matoba S, Tachibana M, Ogura A, Shinkai Y, Nakano T. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature. 2012 Jun 3;486(7403):415-9. doi: 10.1038/nature11093. PMID:22722204 doi:http://dx.doi.org/10.1038/nature11093
↑ Liu N, Wang M, Deng W, Schmidt CS, Qin W, Leonhardt H, Spada F. Intrinsic and extrinsic connections of Tet3 dioxygenase with CXXC zinc finger modules. PLoS One. 2013 May 14;8(5):e62755. PMID:23690950 doi:10.1371/journal.pone.0062755
↑ Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabo PE, Lu Q, Xu GL, Song J, Pfeifer GP. Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell Rep. 2016 Jan 26;14(3):493-505. doi: 10.1016/j.celrep.2015.12.044. Epub 2016, Jan 7. PMID:26774490 doi:http://dx.doi.org/10.1016/j.celrep.2015.12.044
↑ Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabo PE, Lu Q, Xu GL, Song J, Pfeifer GP. Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell Rep. 2016 Jan 26;14(3):493-505. doi: 10.1016/j.celrep.2015.12.044. Epub 2016, Jan 7. PMID:26774490 doi:http://dx.doi.org/10.1016/j.celrep.2015.12.044

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OCA

[1] Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010 Aug 26;466(7310):1129-33. PMID:20639862 doi:10.1038/nature09303

[2] Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun. 2011;2:241. doi: 10.1038/ncomms1240. PMID:21407207 doi:http://dx.doi.org/10.1038/ncomms1240

[3] Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011 Sep 2;333(6047):1300-3. doi: 10.1126/science.1210597. Epub 2011 Jul, 21. PMID:21778364 doi:http://dx.doi.org/10.1126/science.1210597

[4] Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabó PE, Pfeifer GP, Li J, Xu GL. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011 Sep 4;477(7366):606-10. PMID:21892189 doi:10.1038/nature10443

[5] Nakamura T, Liu YJ, Nakashima H, Umehara H, Inoue K, Matoba S, Tachibana M, Ogura A, Shinkai Y, Nakano T. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature. 2012 Jun 3;486(7403):415-9. doi: 10.1038/nature11093. PMID:22722204 doi:http://dx.doi.org/10.1038/nature11093

[6] Liu N, Wang M, Deng W, Schmidt CS, Qin W, Leonhardt H, Spada F. Intrinsic and extrinsic connections of Tet3 dioxygenase with CXXC zinc finger modules. PLoS One. 2013 May 14;8(5):e62755. PMID:23690950 doi:10.1371/journal.pone.0062755

[7] Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabo PE, Lu Q, Xu GL, Song J, Pfeifer GP. Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell Rep. 2016 Jan 26;14(3):493-505. doi: 10.1016/j.celrep.2015.12.044. Epub 2016, Jan 7. PMID:26774490 doi:http://dx.doi.org/10.1016/j.celrep.2015.12.044

[8] Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabo PE, Lu Q, Xu GL, Song J, Pfeifer GP. Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell Rep. 2016 Jan 26;14(3):493-505. doi: 10.1016/j.celrep.2015.12.044. Epub 2016, Jan 7. PMID:26774490 doi:http://dx.doi.org/10.1016/j.celrep.2015.12.044

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