SETD2 explained

SET domain containing 2 is an enzyme that in humans is encoded by the SETD2 gene.^{[1] [2] [3]}

Function

SETD2 protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II.

The trimethylation of lysine-36 of histone H3 (H3K36me3) is required in human cells for homologous recombinational repair and genome stability.^[4] Depletion of SETD2 increases the frequency of deletion mutations that arise by the alternative DNA repair process of microhomology-mediated end joining.

Clinical significance

The SETD2 gene is located on the short arm of chromosome 3 and has been shown to play a tumour suppressor role in human cancer.^[5]

Interactions

SETD2 has been shown to interact with Huntingtin.^[6] Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. SETD2 belongs to a class of huntingtin interacting proteins characterized by WW motifs.

Further reading

• Faber PW, Barnes GT, Srinidhi J, etal . Huntingtin interacts with a family of WW domain proteins . Hum. Mol. Genet. . 7 . 9 . 1463–74 . 1998 . 9700202 . 10.1093/hmg/7.9.1463 . free .
• Passani LA, Bedford MT, Faber PW, etal . Huntingtin's WW domain partners in Huntington's disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington's disease pathogenesis . Hum. Mol. Genet. . 9 . 14 . 2175–82 . 2000 . 10958656 . 10.1093/hmg/9.14.2175 . free .
• Zhang QH, Ye M, Wu XY, etal . Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells . Genome Res. . 10 . 10 . 1546–60 . 2001 . 11042152 . 10.1101/gr.140200 . 310934 .
• Nagase T, Kikuno R, Hattori A, etal . Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Res. . 7 . 6 . 347–55 . 2001 . 11214970 . 10.1093/dnares/7.6.347 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, etal . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 33 . 12130–5 . 2004 . 15302935 . 10.1073/pnas.0404720101 . 514446 . 2004PNAS..10112130B . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Li M, Phatnani HP, Guan Z, etal . Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1 . Proc. Natl. Acad. Sci. U.S.A. . 102 . 49 . 17636–41 . 2006 . 16314571 . 10.1073/pnas.0506350102 . 1308900 . free .
• Lim J, Hao T, Shaw C, etal . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Olsen JV, Blagoev B, Gnad F, etal . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Sun XJ, Wei J, Wu XY, Hu M, Wang L, Wang HH, Zhang QH, Chen SJ, Huang QH, Chen Z . Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase . J Biol Chem . 280 . 42 . 35261–71 . Oct 2005 . 16118227 . 10.1074/jbc.M504012200 . free .
2. Rega S, Stiewe T, Chang DI, Pollmeier B, Esche H, Bardenheuer W, Marquitan G, Putzer BM . Identification of the full-length huntingtin- interacting protein p231HBP/HYPB as a DNA-binding factor . Mol Cell Neurosci . 18 . 1 . 68–79 . Jul 2001 . 11461154 . 10.1006/mcne.2001.1004 . 31658986 .
3. Web site: Entrez Gene: SETD2 SET domain containing 2.
4. Pfister SX, Ahrabi S, Zalmas LP, Sarkar S, Aymard F, Bachrati CZ, Helleday T, Legube G, La Thangue NB, Porter AC, Humphrey TC . SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability . Cell Rep . 7 . 6 . 2006–18 . June 2014 . 24931610 . 4074340 . 10.1016/j.celrep.2014.05.026 .
5. Al Sarakbi W, Sasi W, Jiang WG, Roberts T, Newbold RF, Mokbel K . kefah Mokbel . The mRNA expression of SETD2 in human breast cancer: correlation with clinico-pathological parameters . BMC Cancer . 9 . 290 . 2009 . 19698110 . 3087337 . 10.1186/1471-2407-9-290 . free .
6. Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME . Huntingtin interacts with a family of WW domain proteins . Hum. Mol. Genet. . 7 . 9 . 1463–74 . September 1998 . 9700202 . 10.1093/hmg/7.9.1463 . free .