Histone H3 K56 hyperacetylation perturbs replisomes and causes DNA damage

Ivana Celic, Alain Verreault, Jef D. Boeke

Research output: Contribution to journalArticle

Abstract

Deacetylation of histone H3 K56, regulated by the sirtuins Hst3p and Hst4p, is critical for maintenance of genomic stability. However, the physiological consequences of a lack of H3 K56 deacetylation are poorly understood. Here we show that cells lacking Hst3p and Hst4p, in which H3 K56 is constitutively hyperacetylated, exhibit hallmarks of spontaneous DNA damage, such as activation of the checkpoint kinase Rad53p and upregulation of DNA-damage inducible genes. Consistently, hst3 hst4 cells display synthetic lethality interactions with mutations that cripple genes involved in DNA replication and DNA double-strand break (DSB) repair. In most cases, synthetic lethality depends upon hyperacetylation of H3 K56 because it can be suppressed by mutation of K56 to arginine, which mimics the nonacetylated state. We also show that hst3 hst4 phenotypes can be suppressed by overexpression of the PCNA clamp loader large subunit, Rfc1p, and by inactivation of the alternative clamp loaders CTF18, RAD24, and ELG1. Loss of CTF4, encoding a replisome component involved in sister chromatid cohesion, also suppresses hst3 hst4 phenotypes. Genetic analysis suggests that CTF4 is a part of the K56 acetylation pathway that converges on and modulates replisome function. This pathway represents an important mechanism for maintenance of genomic stability and depends upon proper regulation of H3 K56 acetylation by Hst3p and Hst4p. Our data also suggest the existence of a precarious balance between Rfc1p and the other RFC complexes and that the nonreplicative forms of RFC are strongly deleterious to cells that have genomewide and constitutive H3 K56 hyperacetylation.

Original languageEnglish (US)
Pages (from-to)1769-1784
Number of pages16
JournalGenetics
Volume179
Issue number4
DOIs
StatePublished - Aug 2008

Fingerprint

Histones
DNA Damage
Genomic Instability
Acetylation
Sirtuins
Maintenance
Phenotype
Mutation
Chromatids
Double-Stranded DNA Breaks
Proliferating Cell Nuclear Antigen
DNA Replication
Genes
Arginine
Phosphotransferases
Up-Regulation
Synthetic Lethal Mutations

ASJC Scopus subject areas

  • Genetics

Cite this

Histone H3 K56 hyperacetylation perturbs replisomes and causes DNA damage. / Celic, Ivana; Verreault, Alain; Boeke, Jef D.

In: Genetics, Vol. 179, No. 4, 08.2008, p. 1769-1784.

Research output: Contribution to journalArticle

Celic, Ivana ; Verreault, Alain ; Boeke, Jef D. / Histone H3 K56 hyperacetylation perturbs replisomes and causes DNA damage. In: Genetics. 2008 ; Vol. 179, No. 4. pp. 1769-1784.
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