title: The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα.
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.
authors.affiliation: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Guogen
authors.initials: G
authors.lastname: Mao
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Liya
authors.initials: L
authors.lastname: Gu
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D002843:Chromatin / Q000378:metabolism; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D042421:Histone Code; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein