A Reversible Histone H3 Acetylation Cooperates with Mismatch Repair and Replicative Polymerases in Maintaining Genome Stability

摘要

Mutations are a major driving force of evolution and genetic disease. In eukaryotes, mutations are produced in the chromatin environment, but the impact of chromatin on mutagenesis is poorly understood. Previous studies have determined that in yeast Saccharomyces cerevisiae , Rtt109-dependent acetylation of histone H3 on K56 is an abundant modification that is introduced in chromatin in S phase and removed by Hst3 and Hst4 in G2/M. We show here that the chromatin deacetylation on histone H3 K56 by Hst3 and Hst4 is required for the suppression of spontaneous gross chromosomal rearrangements, base substitutions, 1-bp insertions/deletions, and complex mutations. The rate of base substitutions in hst3 Δ hst4 Δ is similar to that in isogenic mismatch repair-deficient msh2 Δ mutant. We also provide evidence that H3 K56 acetylation by Rtt109 is important for safeguarding DNA from small insertions/deletions and complex mutations. Furthermore, we reveal that both the deacetylation and acetylation on histone H3 K56 are involved in mutation avoidance mechanisms that cooperate with mismatch repair and the proofreading activities of replicative DNA polymerases in suppressing spontaneous mutagenesis. Our results suggest that cyclic acetylation and deacetylation of chromatin contribute to replication fidelity and play important roles in the protection of nuclear DNA from diverse spontaneous mutations. Author Summary Mutations strongly predispose humans to cancer and many other diseases. Despite significant progress, we still do not fully understand the molecular mechanisms that protect us from mutations. Human DNA is part of a highly organized complex called chromatin. Chromatin regulates our development, metabolism, and behavior. Special enzymes modify chromatin by the addition and removal of chemical groups. Acetylation and deacetylation of chromatin have been conserved during evolution. The involvement of chromatin and its modifications in the protection of DNA from mutations is poorly understood. The yeast Saccharomyces cerevisiae is an excellent model for studying the connection between chromatin modifications and mutations. Using this model, we found that the deacetylation and acetylation of chromatin on histone H3 lysine 56 are required for preventing a wide range of spontaneous mutations. Future studies will determine whether acetylation and deacetylation of chromatin are involved in protecting DNA from mutations in human cells.