γH2A/γH2AX Mediates DNA Damage-Specific Control of Checkpoint Signaling in Saccharomyces cerevisiae

DNA lesions trigger DNA damage checkpoint (DDC) signaling which arrests cell cycle progression and promotes DNA damage repair. In Saccharomyces cerevisiae, phosphorylation of histone H2A (gamma H2A, equivalent to gamma H2AX in mammals) is an early chromatin mark induced by DNA damage that is recognized by a group of DDC and DNA repair factors. We find that gamma H2A negatively regulates the G2/M checkpoint in response to the genotoxin camptothecin, which is a DNA topoisomerase I poison. gamma H2A also suppresses DDC signaling induced by the DNA alkylating agent methyl methanesulfonate. These results differ from prior findings, which demonstrate positive or no roles of gamma H2A in DDC in response to other DNA damaging agents such as phleomycin and ionizing radiation, which suggest that gamma H2A has DNA damage-specific effects on DDC signaling. We also find evidence supporting the notion that gamma H2A regulates DDC signaling by mediating the competitive recruitment of the DDC mediator Rad9 and the DNA repair factor Rtt107 to DNA lesions. We propose that gamma H2A/gamma H2AX serves to create a dynamic balance between DDC and DNA repair that is influenced by the nature of DNA damage.