Abstract
The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to γH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression.
Highlights
Recent evidence suggests that histone modifications can affect DNA replication, under both normal or stressed conditions, through effects on nucleosome dynamics and protein recruitment [1,2,3]
We report that coordination of chromatin assembly and checkpoint activity by a histone modification, H2B ubiquitylation (H2Bub), is critical for the cell response to HU-induced replication stress
Our data indicate that H2Bub helps organize DNA in the nuclei during DNA replication; this process plays a similar role to the brakes on a train, serving to slow down replication, and maintaining stable progression of replication under environmental stress
Summary
Recent evidence suggests that histone modifications can affect DNA replication, under both normal or stressed conditions, through effects on nucleosome dynamics and protein recruitment [1,2,3]. One such modification is acetylation of nascent histone H3 at lysine 56 (H3K56Ac), which is regulated by the Asf histone chaperone and the Rtt109 acetyltransferase during the cell cycle [4,5]. H2Bub enhances passage of RNA Polymerase II during transcription elongation by mediating nucleosome reassembly in both yeast and human [20,22,23]. It has been suggested that H2Bub mediates homologous recombination repair at DNA double-strand break (DSB) sites
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