DNA Damage Sensing by the ATM and ATR Kinases

Abstract

In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrated by the ATM and ATR kinases is the central regulator of this network in response to DNA damage. Both ATM and ATR are activated by DNA damage and DNA replication stress, but their DNAdamage specificities are distinct and their functions are not redundant. Furthermore, ATM and ATR often work together to signal DNA damage and regulate downstream processes. Here, we will discuss the recent findings and current models of how ATM and ATR sense DNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR.

Trouble in transitioning: activation of zygotic transcription can lead to DNA breakage and genome instability

“…CHK-1 is phosphorylated and activated by the ATR (ATL-1 in C. elegans) protein kinase during a DNA damage response, and this is an evolutionarily conserved response found in organisms ranging from yeast to man. 12 Using antibodies that recognize the phosphorylated and activated form of CHK-1, we found that CHK-1 was largely inactive in Z2/Z3 in starved L1s, however after feeding the protein was indeed activated, and activation persisted for about an hour before dissipating. 5 This result suggested that a DNA-based signal was being generated, in a nutrientdependent manner, in Z2/Z3 that Figure 1.…”

“…CHK-1 is part of a DNA-based signaling pathway that triggers cell cycle delay in response to DNA replication stress or DNA DSBs. 12 Under our RNAi conditions, chk-1(RNAi) animals are viable however they are also sterile with high penetrance. We opted to pursue the basis for the sterility phenotype, and observed that chk-1(RNAi) adults showed a complete absence of a germline.…”

“…Historically, CHK-1 is activated after either replication stress or DNA DSBs. 12 We could eliminate replication stress as a candidate, because Z2/Z3 finish replication during early embryogenesis, 11 and thus we focused on the possibility that nutrients were triggering DNA DSBs within Z2/Z3 nuclei. One cytological hallmark of DNA DSBs is the appearance of RAD-51 foci.…”

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody–Drug Conjugate for Acute Myeloid Leukemia

“…Accompanying the pH2AX was the phosphorylation and, hence, the activation of the ataxia telangiectasia-mutated (ATM) kinase (p-ATM, Fig. 4A), which is known to trigger the cascade of events leading to cell-cycle arrest as the cells attempt DNA repair (23). Sensing DNA damage response, P53 will be phosphorylated and trigger cell-cycle arrest (24).…”

Complex DSBs: A need for resection

“…The DNA damage responsive protein kinase ATR is recruited to the DNA damage by interacting with the RPA coated ssDNA via its regulatory subunit ATRIP. 5 The authors found ATR was recruited to DSBs induced by high LET treatment and this recruitment was significantly decreased in the absence of Exo1.…”