Control of replication initiation by the Sum1/Rfm1/Hst1 histone deacetylase

BMC Mol Biol. 2008 Nov 6;9:100. doi: 10.1186/1471-2199-9-100.

Abstract

Background: Replication initiation at origins of replication in the yeast genome takes place on chromatin as a template, raising the question how histone modifications, for instance histone acetylation, influence origin firing. Initiation requires binding of the replication initiator, the Origin Recognition Complex (ORC), to a consensus sequence within origins. In addition, other proteins bind to recognition sites in the vicinity of ORC and support initiation. In previous work, we identified Sum1 as an origin-binding protein that contributes to efficient replication initiation. Sum1 is part of the Sum1/Rfm1/Hst1 complex that represses meiotic genes during vegetative growth via histone deacetylation by the histone deacetylase (HDAC) Hst1.

Results: In this study, we investigated how Sum1 affected replication initiation. We found that it functioned in initiation as a component of the Sum1/Rfm1/Hst1 complex, implying a role for histone deacetylation in origin activity. We identified several origins in the yeast genome whose activity depended on both Sum1 and Hst1. Importantly, sum1Delta or hst1Delta caused a significant increase in histone H4 lysine 5 (H4 K5) acetylation levels, but not other H4 acetylation sites, at those origins. Furthermore, mutation of lysines to glutamines in the H4 tail, which imitates the constantly acetylated state, resulted in a reduction of origin activity comparable to that in the absence of Hst1, showing that deacetylation of H4 was important for full initiation capacity of these origins.

Conclusion: Taken together, our results demonstrate a role for histone deacetylation in origin activity and reveal a novel aspect of origin regulation by chromatin. These results suggest recruitment of the Sum1/Rfm1/Hst1 complex to a number of yeast origins, where Hst1 deacetylated H4 K5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • DNA Replication*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Fungal
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism*
  • Histones / genetics
  • Histones / metabolism
  • Mutation
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Origin Recognition Complex / genetics
  • Origin Recognition Complex / metabolism
  • Plasmids / metabolism
  • Repressor Proteins
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sirtuin 2
  • Sirtuins / genetics*
  • Sirtuins / metabolism

Substances

  • DNA-Binding Proteins
  • Histones
  • Nuclear Proteins
  • Origin Recognition Complex
  • Repressor Proteins
  • Rfm1 protein, S cerevisiae
  • SUM1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • HST1 protein, S cerevisiae
  • Sirtuin 2
  • Sirtuins
  • Histone Deacetylases