A reversible histone H3 acetylation cooperates with mismatch repair and replicative polymerases in maintaining genome stability.
A reversible histone H3 acetylation cooperates with mismatch repair and replicative polymerases in maintaining genome stability.
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DOI：
10.1371/journal.pgen.1003899
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发表时间：
2013-10
期刊：
影响因子：
4.5
通讯作者：
Kadyrov FA
中科院分区：
文献类型：
--
作者：
Kadyrova LY;Mertz TM;Zhang Y;Northam MR;Sheng Z;Lobachev KS;Shcherbakova PV;Kadyrov FA
突变是进化和遗传疾病的主要驱动力。在真核生物中，突变是在染色质环境中产生的，但染色质对诱变的影响知之甚少。先前的研究已经确定，在酵母酿酒酵母中，组蛋白H3在K56上的Rtt 109依赖性乙酰化是一种丰富的修饰，其在S期被引入染色质中，并在G2/M期被Hst 3和Hst 4去除。我们在这里表明，染色质脱乙酰化组蛋白H3 K56的HST 3和HST 4是必需的抑制自发的总染色体重排，碱基替换，1-bp的插入/缺失，和复杂的突变。hst 3 Δ hst 4 Δ的碱基替换率与同基因错配修复缺陷型msh 2 Δ突变体相似。我们还提供了证据表明，通过Rtt 109的H3 K56乙酰化对于保护DNA免受小插入/缺失和复杂突变是重要的。此外，我们揭示了组蛋白H3 K56上的去乙酰化和乙酰化都参与了突变避免机制，该机制与错配修复和复制型DNA聚合酶的校对活动合作抑制自发突变。我们的研究结果表明，染色质的环状乙酰化和脱乙酰化有助于复制保真度，并在保护核DNA免受各种自发突变中发挥重要作用。突变使人类极易患上癌症和许多其他疾病。尽管取得了重大进展，但我们仍然没有完全了解保护我们免受突变的分子机制。人类DNA是一个高度组织化的复合体，称为染色质。染色质调节我们的发育、新陈代谢和行为。特殊的酶通过添加和去除化学基团来修饰染色质。染色质的乙酰化和去乙酰化在进化过程中是保守的。染色质及其修饰在保护DNA免受突变中的作用知之甚少。酿酒酵母是研究染色质修饰和突变之间联系的极好模型。使用该模型，我们发现组蛋白H3赖氨酸56上的染色质的脱乙酰化和乙酰化是防止广泛的自发突变所必需的。未来的研究将确定染色质的乙酰化和脱乙酰化是否参与保护人类细胞中的DNA免受突变。
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 hst3Δ hst4Δ is similar to that in isogenic mismatch repair-deficient msh2Δ 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. 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.
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DOI：
10.1126/science.1135862
发表时间：
2007-02-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Driscoll R;Hudson A;Jackson SP
通讯作者：
Jackson SP
影响因子：
10.5
作者：
BRACHMANN, CB;SHERMAN, JM;BOEKE, JD
通讯作者：
BOEKE, JD
影响因子：
16
作者：
Chen, C;Umezu, K;Kolodner, RD
通讯作者：
Kolodner, RD
影响因子：
5.3
作者：
Fillingham, Jeffrey;Recht, Judith;Greenblatt, Jack F.
通讯作者：
Greenblatt, Jack F.
影响因子：
16.8
作者：
通讯作者：
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