Histone H3 K36 Trimethylation Is Required for Mismatch Repair

Mismatch repair (MMR) proteins correct base mispairs caused by incorrect nucleotide incorporation or small insertions and deletions during DNA replication. Loss of MMR gene expression induces a mutator phenotype marked by increased microsatellite instability (MSI) and mutational frequency that predisposes to cancer. However, a subset of MSI-positive cancers express normal levels of MMR genes and appear to be MMR proficient, indicating that other mechanisms underlying MSI remain to be identified. As most MMR studies have been performed in vitro with naked DNA, additional MMR factors are likely needed in vivo in the context of chromatin. Because the MutS homolog 6 (MSH6) subunit of the MutSα MMR complex has a Pro-Trp-Trp-Pro (PWWP) domain capable of recognizing the histone H3 Lys36 trimethylation mark (H3K36me3), Li and colleagues hypothesized that H3K36me3 might play a role in recruiting MutSα to chromatin. Indeed, the MSH6 PWWP domain specifically bound H3K36me3 and was required for formation of MSH6 nuclear foci in cells even though it was not required for MMR in vitro. The majority of MSH6 foci colocalized with H3K36me3, which peaked in abundance in early S-phase, consistent with a role of H3K36me3 in MMR during DNA replication. Knockdown of the H3K36me3 methyltransferase SET domain containing 2 (SETD2) depleted H3K36me3 and significantly reduced MSH6 foci. Moreover, SETD2/H3K36me3–depleted cells showed a significant increase in MSI and mutation frequency, indicating that loss of SETD2 or H3K36me3 confers a mutator phenotype. Notably, several human cancer cell lines with MSI but no known MMR gene mutations or MMR defect in vitro were found to have inactivating SETD2 mutations, H3K36me3 depletion, and diminished S-phase MSH6 foci formation. These findings thus not only provide insight into how MMR occurs in vivo but also offer an explanation for how MSI can occur in the absence of MMR gene mutation.

Li F, Mao G, Tong D, Huang J, Gu L, Yang W, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 2013;153:590–600.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.