Fig. 2

Impact of histone modifications and mutations on MMR. a Under normal circumstances, SETD2 interacts with and trimethylates H3K36. The resulting H3K36me3 recruits MutSα to chromatin by interacting with the PWWP domain in the MSH6 subunit of MutSα. The chromatin-associated MutSα then recognizes mismatches or DNA lesions and triggers downstream MMR reactions to correct the mispairs generated during DNA replication (left) and to remove DNA lesions in the transcribed strand during transcription (right). b When H3G34 is mutated into R, V, or D, the large side chain in these residues creates steric clashes with the cavity of the SETD2 catalytic domain, preventing H3K36 from being trimethylated. In addition, the large side chain also blocks the H3K36me3-MutSα interaction, even if H3K36me3 is available. In both cases, MutSα is not recruited to chromatin, leading to error-prone DNA synthesis and transcription-associated mutations