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Decoding the histone code: Role of H3K36me3 in mismatch repair and implications for cancer susceptibility and therapy
1Author's Affiliations: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky; and Tsinghua University School of Medicine, Beijing, China.
Abstract:
DNA mismatch repair (MMR) maintains genome stability primarily by correcting replication-associated mismatches. Defects in MMR lead to several human cancers characterized by frequent alterations in simple repetitive DNA sequences, a phenomenon called microsatellite instability (MSI). In most MSI-positive cancers, genetic or epigenetic changes that alter the function or expression of an essential MMR protein have been identified. However, in a subset of MSI-positive cancers, epigenetic or genetic changes have not been found in known MMR genes, such that the molecular basis of the MMR defect in these cells remains unknown. A possible answer to this puzzle emerged recently when it was discovered that H3K36me3, a well-studied posttranslational histone modification or histone mark, plays a role in regulating human MMR in vivo. In this review, potential roles for this histone mark to modulate genome stability and cancer susceptibility in human cells are discussed.
Insights
DNA mismatch repair (MMR) maintains genome stability. A histone mark, H3K36me3, was found to regulate MMR in vivo, potentially explaining MMR defects in some human cancers where known MMR genes are unaltered.
Area of Science:
- Genetics
- Epigenetics
- Cancer Biology
Background:
- DNA mismatch repair (MMR) is crucial for maintaining genome stability by correcting DNA replication errors.
- Defects in MMR cause microsatellite instability (MSI), a hallmark of several human cancers.
- The molecular basis for MMR defects remains unknown in a subset of MSI-positive cancers, even when known MMR genes are unaffected.
Purpose of the Study:
- To review the potential roles of the histone mark H3K36me3 in regulating human DNA mismatch repair (MMR).
- To discuss how H3K36me3 may influence genome stability and cancer susceptibility in human cells.
Main Methods:
- This review synthesizes recent findings on the role of H3K36me3 in MMR.
- Literature review of studies investigating histone modifications and DNA repair mechanisms.
Main Results:
- H3K36me3, a posttranslational histone modification, has been identified as a regulator of human MMR in vivo.
- This histone mark offers a potential explanation for MMR defects in cancers lacking alterations in canonical MMR genes.
Conclusions:
- H3K36me3 plays a significant role in modulating genome stability through its regulation of MMR.
- Understanding the function of H3K36me3 in MMR is critical for elucidating the etiology of certain MSI-positive cancers and may reveal new therapeutic targets.
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