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bioRxiv · 10.1101/572271

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

Siler, J.·Huo, N.·Liu, Z.·Qin, Y.·Bi, X.
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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.

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Siler, J., Huo, N., Liu, Z., Qin, Y., Bi, X.. 2019-03-09. DNA damage-specific effects of Tel1/ATM and γH2A/γH2AX on checkpoint signaling in Saccharomyces cerevisiae. https://doi.org/10.1101/572271

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