ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks

Abstract

It is generally thought that the DNA-damage checkpoint kinases, ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), work independently of one another. Here, we show that ATM and the nuclease activity of meiotic recombination 11 (Mre11) are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Moreover, we show that efficient ATM-dependent ATR activation in response to DSBs is restricted to the S and G2 cell cycle phases and requires CDK kinase activity. Thus, in response to DSBs, ATR activation is regulated by ATM in a cell-cycle dependent manner.

Chk2 is required for optimal mitotic delay in response to irradiation-induced DNA damage incurred in G2 phase

“…First, why is Chk2 required for optimal mitotic delay specifically in cells that sustain irradiation-induced DNA damage specifically in G 2 but not in earlier phases of the cell cycle? We suspect that this may relate to recent findings that Chk1 and Chk2 are differentially regulated in response to DNA damage during the cell cycle (Jazayeri et al, 2006). Whereas Chk2 can be activated in all phases of the cell cycle (with the possible exception of mitosis), activation of Chk1 by DNA damage is confined to the S and G 2 phases and does not occur in G 1 (Figure 8).…”

“…In marked contrast to Cds1 in fission yeast, Chk2 is also efficiently activated by DNA damage in vertebrate cells via direct phosphorylation by ATM (Matsuoka et al, 1998;Ahn et al, 2000). Chk1 and Chk2 are however differentially regulated during the cell cycle; whereas Chk2 activation by DNA damage can occur during all phases of the cell cycle and in quiescent cells (Lukas et al, 2001), activation of Chk1 is confined to the S and G 2 phases of proliferating cells (Jazayeri et al, 2006).…”

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

“…Such a sequence has been demonstrated in budding yeast, under the control of the cyclin-dependent kinase CDK1 (Ira et al, 2004). In mammalian cells, resection by MRE11 in S and G2 phase under the control of the kinase ATM (ataxia telangiectasia mutated) and requiring CDK kinase activity has recently been described (Jazayeri et al, 2006). However, in mammalian cells, progression of unrepaired damage in S phase should be deleterious.…”

DNA double-strand break repair and development

“…While there is cross talk between ATM and ATR (Jazayeri et al, 2006;Matsuoka et al, 2007;Yoo et al, 2007), they have separable biochemical roles and complete ATR loss of function, like any of the MRN components, is incompatible with viability (Brown and Baltimore, 2000). Interestingly, NBS shares more in common with ATR-Seckel syndrome than with A-T, despite clear evidence of ATM-Nbs1 interaction (Figure 1).…”