The Role of Histone H4 in Genome Stability

描述（由申请人提供）：细胞在DNA复制偶联事件中经常遇到导致DNA双链断裂和缺陷的条件，这些条件可能来自外部来源，也可能是正常代谢活动的结果。面对这些挑战，保持DNA序列的稳定性对于正常的基因表达、染色体组织和遗传信息的忠实传递至关重要。基因组稳定性的丧失，通过DNA复制缺陷或DNA损伤修复，被认为在致癌和肿瘤进展中起着致病作用。DNA复制和DNA损伤修复都必须在染色质结构的背景下进行，越来越多的证据表明组蛋白修饰对这些过程至关重要。我们已经发现，NuA4组蛋白乙酰转移酶复合物对组蛋白H4的乙酰化是非同源末端连接和复制偶联双链断裂修复所必需的。此外，人类HBO1和酵母Esa1都是MYST组蛋白乙酰转移酶家族的成员，在DNA复制中发挥关键作用。关于组蛋白修饰参与复制和修复功能的分子机制知之甚少。为了解决这些问题，我们将集中研究三个主要问题：(1)组蛋白修饰如何在双链断裂位点起作用以及组蛋白修饰突变体中存在缺陷的分子步骤；(2)乙酰化在DNA复制起始和延伸中的分子作用；(3)维持基因组稳定性的组蛋白依赖通路的功能基因组学。

DESCRIPTION (provided by applicant): Cells routinely encounter conditions that cause DNA double-strand breaks and defects in DNA replication-coupled events, both from external sources and as a result of normal metabolic activity. Maintaining DNA sequence stability in face of these challenges is essential for normal gene expression, chromosome organization, and faithful transmission of genetic information. Loss of genome stability, through defects in DNA replication or DNA damage repair, is thought to play a causative role in carcinogenesis and tumor progression. Both DNA replication and DNA damage repair must take place in the context of chromatin structure and there is increasing evidence that histone modifications are essential for these processes. We have discovered that acetylation of histone H4 by the NuA4 histone acetyltransferase complex is required for nonhomologous end-joining and replication-coupled double-strand break repair. Furthermore, both human HBO1 and yeast Esa1, members of the MYST family of histone acetyltransferases, play key roles in DNA replication. Little is known about the molecular mechanisms by which histone modifications participate in replication and repair functions. To address these issues we will focus on three major research questions: (1) how histone modification functions at the site of a double-strand break and the molecular steps that are defective in histone modification mutants; (2) the molecular role of acetylation in DNA replication initiation and elongation; and (3) the functional genomics of the histone-dependent pathways that maintain genome stability.