The conserved histone chaperone Spt6 facilitates DNA replication and mediates genome stability

Abstract

Histone chaperones are an important class of proteins that regulate chromatin accessibility for DNA-templated processes, such as transcription and DNA replication. Spt6 is a conserved histone chaperone and a key regulator of transcription and chromatin structure. However, its functions outside of these roles have been little explored. In Chapter 2, we demonstrate a role for S. cerevisiae Spt6 in DNA replication and more broadly as a regulator of genome stability. Spt6 binds the replication machinery and depletion or mutation of Spt6 impairs DNA replication in vivo. Additionally, spt6 mutants are sensitive to DNA replication stress inducing agents, with increased sensitivity when combined with loss of DNA replication associated factors. Furthermore, spt6 mutants have elevated levels of DNA double strand breaks and recombination. These effects appear to be independent of genotoxic RNA-DNA hybrids (R-loops), which are not elevated in spt6 mutants. Our results identify Spt6 as a regulator of genome stability, at least in part through a role in DNA replication.