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

  title={ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks},
  author={Ali Jazayeri and Jacob Falck and Claudia Lukas and Jiri Bartek and Graeme C.M. Smith and Jiri Lukas and Stephen P. Jackson},
  journal={Nature Cell Biology},
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… 

ATM regulates ATR chromatin loading in response to DNA double-strand breaks

Experimental evidence is provided of an active cross talk between ATM and ATR signaling pathways in response to DNA damage, which places ATM activity upstream of ATR recruitment to IR-damaged chromatin.

"ATR activation in response to ionizing radiation: still ATM territory"

The canonical model, ATM and ATR are activated by various forms of DNA damage, including DSBs, arising at stalled replication forks ("replication stress"), and ATM is responsible for the signaling of D SBs that are not associated with the replication machinery throughout the cell cycle.

ATM, ATR and DNA damage-induced cell cycle arrest

This review mainly focuses on the roles they play in DNA damage-mediated cell cycle arrest, and the crosstalk of these two protein kinases.

Interplay between ATM and ATR for the regulation of cellular responses to DNA damage

Flow cytometry-based measurement of DNA-content and mitotic index variations are used to detect G2 checkpoint activation and maintenance after exposure of cells with different genetic background to ionizing radiation (IR).

in response to DNA double-strand breaks

Experimental evidence is provided of an active cross talk between ATM and ATR signaling pathways in response to DNA damage, which places ATM activity upstream of ATR recruitment to IR-damaged chromatin.

Distinct roles of ATR and DNA‐PKcs in triggering DNA damage responses in ATM‐deficient cells

It is reported that the crucial checkpoint signalling proteins—p53, structural maintainance of chromosomes 1 (SMC1), p53 binding protein 1 (53BP1), checkpoint kinase (Chk)1 and Chk2—are phosphorylated rapidly by ATR in an ATM/Mre11/cell‐cycle‐independent manner, albeit at low levels.

ATM’s Role in the Repair of DNA Double-Strand Breaks

The roles of ATM that focus on DSB repair are summarized, leading to dramatic sensitivity to ionizing radiation in ataxia telangiectasia (A-T) cells.

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

It is shown that activation of the checkpoint effector kinase Chk1 in response to irradiation-induced DNA damage is minimal in G1, maximal during S-phase and diminishes as cells enter G2, and substitution of S286 and S301 with non-phosphorylatable alanine residues strongly attenuates DNA damage-induced Chk 1 activation and G2 checkpoint proficiency, but does not eliminate the underlying cell cycle dependence of Chk2 regulation.

DNA Damage-Sensing Kinases Mediate the Mouse 2-Cell Embryo's Response to Genotoxic Stress1

The results show, to the authors' knowledge for the first time, that the G2-M and G1-S cell-cycle checkpoints in the early embryo are differentially regulated by ATM and ATR in response to genotoxic stress and that they act as an initial point for containment of genomic damage.



ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex

The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.

Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage

Findings reveal that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signalling.

ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses

It is demonstrated that ATR/ATM-dependent phosphorylation of hRad17 is a critical early event during checkpoint signalling in DNA-damaged cells.

Phosphorylation of serines 635 and 645 of human Rad17 is cell cycle regulated and is required for G1/S checkpoint activation in response to DNA damage

It is demonstrated that ATR but not ATM phosphorylates the human Rad17 (hRad17) checkpoint protein on Ser635 and Ser645 in vitro, suggesting ATR and hRad17 are essential components of a DNA damage response pathway in mammalian cells.

ATR and ATRIP: Partners in Checkpoint Signaling

The identification of an ATR-interacting protein (ATRIP) that is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway is reported.

Requirement of the MRN complex for ATM activation by DNA damage

It is shown that functional MRN is required for ATM activation, and consequently for timely activation of ATM‐mediated pathways, and explain the clinical resemblance between A‐T and A-TLD.

The DNA damage-dependent intra–S phase checkpoint is regulated by parallel pathways

It is concluded that in response to ionizing radiation, phosphorylations of Nbs1 and Chk2 by ATM trigger two parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.

Chk2 Activation Dependence on Nbs1 after DNA Damage

It is shown that the ATM-dependent activation of Chk2 by γ- radiation requires Nbs1, the gene product involved in the Nijmegen breakage syndrome (NBS), a disorder that shares with AT a variety of phenotypic defects including chromosome fragility, radiosensitivity, and radioresistant DNA synthesis, and suggest that checkpoint defects in NBS cells may result from the inability to activate Chk1.

Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage.

It is shown that the protein kinase, Atm, which belongs to a family of phosphatidylinositol 3-kinases that regulate cell cycle checkpoints and DNA recombination and repair, phosphorylates Smc1 protein after ionizing irradiation.