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.
