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PMID: 16141196 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Reduction of nucleosome assembly during new DNA synthesis impairs both major pathways of double-strand break repair.

Nucleic acids research ·Vol. 33 ·No. 15 ·2005-00-00 ·Pages 4928-39

Lewis LK, Karthikeyan G, Cassiano J, Resnick MA

Abstract

Assembly of new chromatin during S phase requires the histone chaperone complexes CAF-1 (Cac2p, Msi1p and Rlf2p) and RCAF (Asf1p plus acetylated histones H3 and H4). Cells lacking CAF-1 and RCAF are hypersensitive to DNA-damaging agents, such as methyl methanesulfonate and camptothecin, suggesting a possible defect in double-strand break (DSB) repair. Assays developed to quantitate repair of defined, cohesive-ended break structures revealed that DSB-induced plasmid:chromosome recombination was reduced approximately 10-fold in RCAF/CAF-1 double mutants. Recombination defects were similar with both chromosomal and plasmid targets in vivo, suggesting that inhibitory chromatin structures were not involved. Consistent with these observations, ionizing radiation-induced loss of heterozygosity was abolished in the mutants. Nonhomologous end-joining (NHEJ) repair proficiency and accuracy were intermediate between wild-type levels and those of NHEJ-deficient yku70 and rad50 mutants. The defects in NHEJ, but not homologous recombination, could be rescued by deletion of HMR-a1, a component of the a1/alpha2 transcriptional repressor complex. The findings are consistent with the observation that silent mating loci are partially derepressed. These results demonstrate that defective assembly of nucleosomes during new DNA synthesis compromises each of the known pathways of DSB repair and that the effects can be indirect consequences of changes in silenced chromatin structure.

MeSH Terms
Cell Cycle Proteins/genetics Chromatin Assembly Factor-1 Chromosomal Proteins, Non-Histone/genetics DNA Damage DNA Repair DNA Replication DNA, Fungal/biosynthesis,radiation effects DNA-Binding Proteins/genetics Histones/genetics Loss of Heterozygosity Molecular Chaperones Mutagens/toxicity Mutation Nucleosomes/chemistry,metabolism Radiation, Ionizing Recombination, Genetic Saccharomyces cerevisiae Proteins/genetics
Chemicals
ASF1 protein, S cerevisiae Cell Cycle Proteins Chromatin Assembly Factor-1 Chromosomal Proteins, Non-Histone DNA, Fungal DNA-Binding Proteins Histones Molecular Chaperones Mutagens Nucleosomes Saccharomyces cerevisiae Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Lewis L Kevin
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA. LL18@txstate.edu
Karthikeyan G
Cassiano Jared
Resnick Michael A
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gki806
Email
ll18@txstate.edu
Published
2005-00-00
Epub
2005-00-01
Pages
4928-39
Language
English
Region
England
NLM ID
0411011
PMCID
PMC1197131
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/gki806 PMC Full Text View journal details
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