Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage.
Cells maintain genomic stability by the coordination of DNA-damage repair and cell-cycle checkpoint control. In replicating cells, DNA damage usually activates intra-S-phase checkpoint controls, which are characterized by delayed S-phase progression and increased Rad53 phosphorylation. We show that in budding yeast, the intra-S-phase checkpoint controls, although functional, are not activated by the topoisomerase I inhibitor camptothecin (CPT). In a CPT-hypersensitive mutant strain that lacks the histone 2A (H2A) phosphatidylinositol-3-OH kinase (PI(3)K) motif at Ser 129 (h2a-s129a), the hypersensitivity was found to result from a failure to process full-length chromosomal DNA molecules during ongoing replication. H2A Ser 129 is not epistatic to the RAD24 and RAD9 checkpoint genes, suggesting a non-checkpoint role for the H2A PI(3)K site. These results suggest that H2A Ser 129 is an essential component for the efficient repair of DNA double-stranded breaks (DSBs) during replication in yeast, particularly of those DSBs that do not induce the intra-S-phase checkpoint.
Redon
Christophe
C
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Pilch
Duane R
DR
Rogakou
Emmy P
EP
Orr
Ann H
AH
Lowndes
Noel F
NF
Bonner
William M
WM
D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology; D015825:Chromosomes, Fungal / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D004260:DNA Repair / Q000502:physiology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D016521:Electrophoresis, Gel, Pulsed-Field; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors
D006657:Histones; D059004:Topoisomerase I Inhibitors; D012694:Serine; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin