DNA damage-specific effects of Tel1/ATM and γH2A/γH2AX on checkpoint signaling in Saccharomyces cerevisiae

Abstract

DNA lesions trigger the activation of DNA damage checkpoints (DDCs) that stop cell cycle progression and promote DNA damage repair. Saccharomyces cerevisiae Tel1 is a homolog of mammalian ATM kinase that plays an auxiliary role in DDC signaling. {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 both Tel1 and {gamma}H2A negatively impact G2/M checkpoint in response to DNA topoisomerase I poison camptothecin independently of each other. {gamma}H2A also negatively regulates DDC induced by DNA alkylating agent methyl methanesulfonate. These results, together with prior findings demonstrating positive or no roles of Tel1 and {gamma}H2A in DDC in response to other DNA damaging agents such as phleomycin and ionizing radiation, suggest that Tel1 and {gamma}H2A have DNA damage-specific effects on DDC. We present data indicating that Tel1 acts in the same pathway as Mre11-Rad50-Xrs2 complex to suppress CPT induced DDC possibly by repairing topoisomerase I-DNA crosslink. On the other hand, we find evidence consistent with the notion that {gamma}H2A regulates DDC by mediating the competitive recruitment of DDC mediator Rad9 and DNA repair factor Rtt107 to sites of DNA damage. We propose that {gamma}H2A serves to create a dynamic balance between DDC and DNA repair that is influenced by the nature of DNA damage.