Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin

Zou, Lee; Chen, David; Elledge, Stephen J.

doi:10.1101/gad.950302

Cited by 470 publications

(513 citation statements)

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“…Consistent with earlier reports, HU treatment did not alter chromatin association of Rad17 and ATR (Zou et al, 2002;Dart et al, 2004); the FEM1B downregulation resulted in a slight decrease in chromatin-associated Rad17, but no detectable change in ATR (Figure 4b). In contrast, a marked decrease in Rad9 in chromatin fraction (P2), but not in soluble nuclear fraction (S2) was observed when FEM1B was ablated by targeting siRNA (Figure 4b).…”

Section: Fem1b As a Novel Chk1 Mediatorsupporting

confidence: 92%

“…Binding of the RPA then recruits and activates the ATR/ATRIP complex (Zou and Elledge, 2003), resulting in the phosphorylation and activation of downstream mediators and effectors. On the other hand, the 9-1-1 complex is independently loaded onto stalled sites by the Rad17-replication factor C (RFC) complex (Zou et al, 2002). The reason why two independent-sensor complexes are needed is not entirely clear.…”

Section: Introductionmentioning

confidence: 99%

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Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Shieh

2009

Oncogene

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Human checkpoint kinase 1 (CHK1) is an essential kinase required to preserve genome stability, and is activated by DNA replication blockage through the ataxia-telangiectasia-mutated-and-Rad3-related (ATR)/ATRIP-signaling pathway. In this report, we show that a novel CHK1-interacting protein, FEM1B (human homologue of the Caenorhabditis elegans sex determination fem1 protein), identified by a yeast two-hybrid screen, is involved in the activation of CHK1 by replication stress. Depletion of FEM1B by small interfering RNA in cancer cells impairs the activation of CHK1 kinase activity and attenuates the induction of CHK1 Ser345 phosphorylation upon replication interference. It is to be noted that, CHK2 Thr68 phosphorylation is not altered by FEM1B downregulation. By fractionation, we further demonstrated that FEM1B is able to associate with chromatin, and such association facilitates chromatin loading of the Rad9 protein. Consistently, ATR activity is poorly maintained in FEM1B knockdown cells; and FEM1B-ablated cells are as sensitive to replication block as CHK1-depleted cells. Our study has uncovered an adaptor protein FEM1B, which acts as a bridge linking CHK1 and Rad9, thus facilitating checkpoint signaling induced by replication stress.

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Section: Fem1b As a Novel Chk1 Mediatorsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Shieh

2009

Oncogene

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“…Replication protein A-coated DNA recruits ATR together with its interacting protein ATRIP (Zou and Elledge, 2003). Full activation of the ATR/ATRIP complex and successful checkpoint function requires loading of the sensor Rad17 and 9-1-1 (Rad9, Rad1, and Hus1) complexes onto DNA (Zou et al, 2002).…”

Section: Molecular Components Of the Dna Damage Checkpointsmentioning

confidence: 99%

G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer

2008

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Rigorous quality control steps, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate functional cellular checkpoints. These checkpoints can facilitate DNA repair and promote cell death in unrepaired cells. There are at least three DNA damage checkpoints -at G1/S, S, and G2/M -as well as a mitotic spindle checkpoint. Most cancer cells harbour mutations in tumour suppressors and/or oncogenes, which impair certain cell checkpoints. Inhibiting the remaining cell checkpoints -particularly after exposure of cancer cells to chemotherapy and/or radiation -allows cell death, a strategy now being employed in cancer therapeutics. With our increasing knowledge of cell cycle regulation, many compounds have been developed to inhibit specific checkpoint components, particularly at the G2/M transition. One such target is checkpoint kinase-1 (Chk1). We review here the molecular framework of the cell cycle, the rationale for targeting Chk1, the preclinical concepts related to the development of Chk1 inhibitors, and the efficacy and safety results from Chk1 inhibitors now in phase I/II trials. British Journal of Cancer (2008) The cell cycle is organised into a series of dependent pathways, whereby the initiation of each event is dependent upon successful completion of previous events. In this way, replicating cells traverse the four distinct phases of the cell cycle consecutively: G1 followed by S, followed by G2 and, finally, M. This ordered progression is guarded by checkpoints capable of delaying the cell cycle in response to intra-or extracellular stressors. As part of the cell cycle surveillance system, the DNA damage and spindle checkpoints protect the cell from genomic instability. Checkpoints are important quality control measures that ensure the proper sequence of cell cycle events and allow cells to respond to DNA damage.Increasingly, checkpoint inhibition has become an area of novel drug development. In the setting of DNA damage, checkpoint inhibition leads to genomic instability, and subsequent cell death. The first checkpoint, found at the G1/S transition, is compromised in many malignant cells, due to mutations in various tumour suppressor genes, including retinoblastoma protein (Rb) and p53. Cells deficient in the G1 checkpoint are dependent on the S and G2 checkpoints for DNA repair. Checkpoint kinase-1 (Chk1) is an active transducer kinase at both the S and G2 checkpoints, rendering it a target for rational anticancer drug development. In the presence of DNA damage, Chk1 inactivation abrogates G2 arrest, resulting in preferential cancer cell death .This article serves to review the (1) current molecular pathways comprising the cell cycle checkpoint machinery, (2) inhibition of Chk1 as an effective means of abrogating G2 arrest, and (3) current Chk1 inhibitors in use in phase I clinical trials.

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“…These two complexes are thus reminiscent of the 'clamp loader' and the 'sliding clamp' involved in DNA replication, 3 and recent evidence suggests that a similar mechanism might be used to load the 9-1-1 complex onto sites of DNA damage. 4 A third protein complex, known as the Mre11-Rad50-Nbs1 complex (MRN), Mre11¼meiotic recombination 11; Nbs1 nibrin (mutated in Nijmegen breakage syndrome), also localizes to sites of double-strand breaks; this complex furthermore has a role in repair, meiotic recombination and telomere maintenance. Mutants for the Mre11 or Nbs1 proteins exhibit a radioresistant DNA synthesis (RDS) phenotype, indicating that these proteins are also involved in checkpoints during S-phase of the cell cycle.…”

Section: Dna Damage Response Proteins: Sensors Transducers and Effecmentioning

confidence: 99%

Death and more: DNA damage response pathways in the nematode C. elegans

2003

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Genotoxic stress is a threat to our cells' genome integrity. Failure to repair DNA lesions properly after the induction of cell proliferation arrest can lead to mutations or large-scale genomic instability. Because such changes may have tumorigenic potential, damaged cells are often eliminated via apoptosis. Loss of this apoptotic response is actually one of the hallmarks of cancer. Towards the effort to elucidate the DNA damage-induced signaling steps leading to these biological events, an easily accessible model system is required, where the acquired knowledge can reveal the mechanisms underlying more complex organisms. Accumulating evidence coming from studies in Caenorhabditis elegans point to its usefulness as such. In the worm's germline, DNA damage can induce both cell cycle arrest and apoptosis, two responses that are spatially separated. The latter is a tightly controlled process that is genetically indistinguishable from developmental programmed cell death. Upstream of the central death machinery, components of the DNA damage signaling cascade lie and act either as sensors of the lesion or as transducers of the initial signal detected. This review summarizes the findings of several studies that specify the elements of the DNA damage-induced responses, as components of the cell cycle control machinery, the repairing process or the apoptotic outcome. The validity of C. elegans as a tool to further dissect the complex signaling network of these responses and the high potential for it to reveal important links to cancer and other genetic abnormalities are addressed.

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Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin

Cited by 470 publications

References 39 publications

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer

Death and more: DNA damage response pathways in the nematode C. elegans

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