Wss1 Promotes Replication Stress Tolerance by Degrading Histones

Abstract

Summary: Timely completion of DNA replication is central to accurate cell division and to the maintenance of genomic stability. However, certain DNA-protein interactions can physically impede DNA replication fork progression. Cells remove or bypass these physical impediments by different mechanisms to preserve DNA macromolecule integrity and genome stability. In Saccharomyces cerevisiae, Wss1, the DNA-protein crosslink repair protease, allows cells to tolerate hydroxyurea-induced replication stress, but the underlying mechanism by which Wss1 promotes this function has remained unknown. Here, we report that Wss1 provides cells tolerance to replication stress by directly degrading core histone subunits that non-specifically and non-covalently bind to single-stranded DNA. Unlike Wss1-dependent proteolysis of covalent DNA-protein crosslinks, proteolysis of histones does not require Cdc48 nor SUMO-binding activities. Wss1 thus acts as a multi-functional protease capable of targeting a broad range of covalent and non-covalent DNA-binding proteins to preserve genome stability during adverse conditions. : Maddi et al. show that Wss1 degrades unincorporated histones to tolerate replication stress. Wss1 is a DNA-dependent metalloprotease that cleaves DNA-protein crosslinks to maintain genome stability. Unlike DNA-protein crosslink removal, Wss1 does not require interactions with Sumo or Cdc48 to act on histones that bind non-specifically to DNA. Keywords: Wss1, metalloprotease, hydroxyurea, HU, histone H3, histone H2A, histone H4, Ddi1, Rad51, replication stress, DNA-protein crosslinks