Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex

Adams, K. E.; Medhurst, Annette L.; Dart, Dafydd Alwyn; Lakin, Nicholas D.

doi:10.1038/sj.onc.1209426

Cited by 143 publications

(142 citation statements)

References 63 publications

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“…Although the localization and activation of ATR at DSB sites has been detected in cyclin A-positive cells in S-and G 2 -phase cells (Jazayeri et al, 2006), there is also evidence indicating that ATR might be activated before the onset of DNA synthesis (Adams et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in yeast (Cha and Kleckner, 2002) and Xenopus (Shechter et al, 2004) model systems have shown that ATR homologs function at active replicons to suppress DNA breaks and prevent fork stalling. Recent reports have demonstrated that ATR is activated at double-strand DNA break (DSB) sites, suggesting that ATR contributes to IR responses in human cells (Adams et al, 2006;Cuadrado et al, 2006;Jazayeri et al, 2006;Myers and Cortez, 2006). These reports have shown that ATR colocalizes with phosphorylated Chk1 at sites of DSBs (Adams et al, 2006;Jazayeri et al, 2006) and that Chk1 phosphorylation after IR exposure is largely ATRdependent.…”

Section: Introductionmentioning

confidence: 99%

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Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

2006

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The vast majority of cancer cells have defective checkpoints that permit the cell cycle to progress in the presence of double-strand DNA breaks (DSBs) caused by ionizing radiation (IR) and radiomimetic drugs. ATR (ataxia telangiectasia-mutated and Rad3-related) has recently been shown to be activated by DSBs, although the consequences of this activity are largely unknown. In this report, we use advanced gene targeting methods to generate biallelic hypomorphic ATR mutations in human colorectal cancer cells and demonstrate that progression of the cancer cell cycle after IR treatment requires ATR. Cells with mutant ATR accumulated at a defined point at the beginning of the S phase after IR treatment and were unable to progress beyond that point, whereas cells at later stages of the S phase during the time of irradiation progressed and completed DNA replication. The prolonged arrest of ATR mutant cancer cells did not involve the ataxia telangiectasia mutated-dependent S-phase checkpoint, but rather closely resembled a previously characterized form of cell cycle arrest termed S-phase stasis. As ATR strongly contributed to clonogenic survival after IR treatment, these data suggest that blocking ATR activity might be a useful strategy for inducing S-phase stasis and promoting the radiosensitization of checkpointdeficient cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

2006

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“…The resulting ssDNA coated by RPA, then initiates ATR signalling (Jazayeri et al, 2006). Studies by Cuadrado et al, Yoo et al, and Adams et al, have provided further experimental evidence to support ATM dependent activation of ATR is required in double strand break DNA repair (Cuadrado et al, 2006;Yoo et al, 2007;Adams et al, 2006). Importantly, ATR has also been shown to activate ATM in response to the presence of ssDNA damage (Stiff et al, 2006).…”

Section: Atr Activation In Response To Single Strand Dna Damagementioning

confidence: 93%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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“…Additional evidence in support of this was reported by Zhang et al (2005) who showed that the MRN complex is required for ATR-dependent phosphorylation of SMC1; for cell survival; the intra-S-phase checkpoint and genomic stability after exposure to UV. Furthermore, recruitment of ATR to sites of radiation-induced DNA damage and activation requires ATM and components of the MRN complex (Adams et al, 2006;Myers and Cortez, 2006).…”

Section: Viral Infection and In Vitro Models To Investigate The Role mentioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

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Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex

Cited by 143 publications

References 63 publications

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

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