Beyond heterochromatin: SIR2 inhibits the initiation of DNA replication

Over the last decade, data have accumulated that support a role for chromatin structure in regulating the initiation of DNA replication and its timing during S-phase. However, the mechanisms underlying how chromatin structure influences replication initiation are not always understood. For example, in Drosophila histone acetylation at the ACE3 and Ori-beta sequences near one of the amplified chorion loci is correlated with ORC (origin recognition complex) binding and re-replication of this locus. Whether histone acetylation promotes ORC binding or some later step in replication is not known. In yeast, hypo-acetylated heterochromatin and telomeric regions replicate late in S-phase but the mechanisms that restrict the initiation of replication at these loci are not fully understood. Nonetheless, it seems likely that histone acetylation and other types of histone modification will significantly impact DNA replication. A recent study published in Molecular Cell reveals a role for the conserved NAD(+)-dependent histone deacetylase, Sir2, in inhibiting the assembly of the multiprotein complex necessary for the selection and activation of yeast replication origins. Here, we highlight key conclusions from this study, place them in perspective with earlier work, and outline important future questions.