The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα

Feng Li, Guogen Mao, Dan Tong, Jian Huang, Liya Gu, Wei Yang, Guo Min Li

Research output: Contribution to journalArticle

279 Scopus citations

Abstract

DNA mismatch repair (MMR) ensures replication fidelity by correcting mismatches generated during DNA replication. Although human MMR has been reconstituted in vitro, how MMR occurs in vivo is unknown. Here, we show that an epigenetic histone mark, H3K36me3, is required in vivo to recruit the mismatch recognition protein hMutSα (hMSH2-hMSH6) onto chromatin through direct interactions with the hMSH6 PWWP domain. The abundance of H3K36me3 in G1 and early S phases ensures that hMutSα is enriched on chromatin before mispairs are introduced during DNA replication. Cells lacking the H3K36 trimethyltransferase SETD2 display microsatellite instability (MSI) and an elevated spontaneous mutation frequency, characteristic of MMR-deficient cells. This work reveals that a histone mark regulates MMR in human cells and explains the long-standing puzzle of MSI-positive cancer cells that lack detectable mutations in known MMR genes.

Original languageEnglish (US)
Pages (from-to)590-600
Number of pages11
JournalCell
Volume153
Issue number3
DOIs
StatePublished - Apr 25 2013

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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