TY - JOUR
T1 - H3K36me3-mediated mismatch repair preferentially protects actively transcribed genes from mutation
AU - Huang, Yaping
AU - Gu, Liya
AU - Li, Guo Min
N1 - Publisher Copyright:
© 2018 Huang et al.
PY - 2018/5/18
Y1 - 2018/5/18
N2 - Histone H3 trimethylation at lysine 36 (H3K36me3) is an important histone mark involved in both transcription elongation and DNA mismatch repair (MMR). It is known that H3K36me3 recruits the mismatch-recognition protein MutS to replicating chromatin via its physical interaction with MutS’s PWWP domain, but the exact role of H3K36me3 in transcription is undefined. Using ChIP combined with whole-genome DNA sequencing analysis, we demonstrate here that H3K36me3, together with MutS, is involved in protecting against mutation, preferentially in actively transcribed genomic regions. We found that H3K36me3 and MutS are much more co-enriched in exons and actively transcribed regions than in introns and nontranscribed regions. The H3K36me3–MutS co-enrichment correlated with a much lower mutation frequency in exons and actively transcribed regions than in introns and nontranscribed regions. Correspondingly, depleting H3K36me3 or disrupting the H3K36me3–MutS interaction elevated the spontaneous mutation frequency in actively transcribed genes, but it had little influence on the mutation frequency in nontranscribed or transcriptionally inactive regions. Similarly, H2O2-induced mutations, which mainly cause base oxidations, preferentially occurred in actively transcribed genes in MMR-deficient cells. The data presented here suggest that H3K36me3-mediated MMR preferentially safeguards actively transcribed genes not only during replication by efficiently correcting mispairs in early replicating chromatin but also during transcription by directly or indirectly removing DNA lesions associated with a persistently open chromatin structure.
AB - Histone H3 trimethylation at lysine 36 (H3K36me3) is an important histone mark involved in both transcription elongation and DNA mismatch repair (MMR). It is known that H3K36me3 recruits the mismatch-recognition protein MutS to replicating chromatin via its physical interaction with MutS’s PWWP domain, but the exact role of H3K36me3 in transcription is undefined. Using ChIP combined with whole-genome DNA sequencing analysis, we demonstrate here that H3K36me3, together with MutS, is involved in protecting against mutation, preferentially in actively transcribed genomic regions. We found that H3K36me3 and MutS are much more co-enriched in exons and actively transcribed regions than in introns and nontranscribed regions. The H3K36me3–MutS co-enrichment correlated with a much lower mutation frequency in exons and actively transcribed regions than in introns and nontranscribed regions. Correspondingly, depleting H3K36me3 or disrupting the H3K36me3–MutS interaction elevated the spontaneous mutation frequency in actively transcribed genes, but it had little influence on the mutation frequency in nontranscribed or transcriptionally inactive regions. Similarly, H2O2-induced mutations, which mainly cause base oxidations, preferentially occurred in actively transcribed genes in MMR-deficient cells. The data presented here suggest that H3K36me3-mediated MMR preferentially safeguards actively transcribed genes not only during replication by efficiently correcting mispairs in early replicating chromatin but also during transcription by directly or indirectly removing DNA lesions associated with a persistently open chromatin structure.
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U2 - 10.1074/jbc.RA118.002839
DO - 10.1074/jbc.RA118.002839
M3 - Article
C2 - 29610279
AN - SCOPUS:85047357254
SN - 0021-9258
VL - 293
SP - 7811
EP - 7823
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -