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Updated: May 8, 2026
Examination of Proteins Bound to Nascent DNA in Mammalian Cells Using BrdU-ChIP-Slot-Western Technique
Published on: January 15, 2016
The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα
Feng Li1, Guogen Mao, Dan Tong
1Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
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.
Insights
An epigenetic histone mark, H3K36me3, recruits DNA mismatch repair proteins to chromatin in vivo. This finding explains microsatellite instability in cancers lacking MMR gene mutations.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- DNA mismatch repair (MMR) is crucial for replication fidelity.
- The in vivo mechanisms of human MMR remain largely unknown.
- Microsatellite instability (MSI) is a hallmark of MMR deficiency, often observed in cancers.
Purpose of the Study:
- To elucidate the in vivo mechanism of human DNA mismatch repair.
- To investigate the role of epigenetic modifications in MMR recruitment.
- To explain the cause of MSI in cancers with no detectable MMR gene mutations.
Main Methods:
- Investigated the interaction between histone marks and MMR proteins in vivo.
- Utilized chromatin immunoprecipitation and genetic analysis.
- Examined cells lacking the SETD2 methyltransferase.
Main Results:
- The epigenetic histone mark H3K36me3 directly recruits the hMutSα complex to chromatin via the hMSH6 PWWP domain.
- H3K36me3 enrichment during G1 and early S phases ensures hMutSα presence before DNA replication.
- SETD2-deficient cells exhibit MSI and increased mutation frequency, mirroring MMR-deficient phenotypes.
Conclusions:
- Histone mark H3K36me3 is essential for recruiting MMR proteins in vivo.
- This epigenetic regulation provides a mechanism for MMR surveillance.
- The study resolves the paradox of MSI in cancers with wild-type MMR genes.
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