Histone h3 k56 hyperacetylation perturbs replisomes and causes DNA damage.

Histone h3 k56 hyperacetylation perturbs replisomes and causes DNA damage. Research Abstract Details 

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Histone h3 k56 hyperacetylation perturbs replisomes and causes DNA damage. Abstract Text:

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.

Histone h3 k56 hyperacetylation perturbs replisomes and causes DNA damage. Publishing Authors By Initials

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Histone h3 k56 hyperacetylation perturbs replisomes and causes DNA damage. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Genetics

VOLUME: 179

Page Numbers: 1769-84

Journal Abbreviation: Genetics

ISSN: 0016-6731

DAY: 24

MONTH: 06

YEAR: 2008

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LANGUAGE: eng

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AFFILIATION: Institute for Research in Immunology and Cancer, Département de Pathologie et de Biologie Cellulaire, Université de Montreal, Montreal, Quebec H3C 3J7, Canada.

Country: United States

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MEDLINETA: Genetics

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