Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex

Grenon, Muriel; Gilbert, Chris; Lowndes, Noel F.

doi:10.1038/ncb0901-844

Cited by 166 publications

(143 citation statements)

References 28 publications

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“…Analysis of ATM activation and substrates such as SMC1 showed that the ATM signalling cascade was activated in these treatments and was affected by tungstate [3]. The MRN complex has diverse functions in DNA damage recognition [34], cell cycle checkpoint activation [35], non-homologous end joining [36] and telomere maintenance [37]. The MRN complex binds DSB soon after they are formed implicating it in DNA damage detection [38], thus acting upstream ATM and allowing its activation.…”

Section: Discussionmentioning

confidence: 99%

Sodium tungstate modulates ATM function upon DNA damage

et al. 2013

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Edited by Varda RotterKeywords: DNA damage Antitumoral Double-strand break Phosphatase inhibition a b s t r a c t Both radiotherapy and most effective chemotherapeutic agents induce different types of DNA damage. Here we show that tungstate modulates cell response to DNA damaging agents. Cells treated with tungstate were more sensitive to etoposide, phleomycin and ionizing radiation (IR), all of which induce DNA double-strand breaks (DSBs). Tungstate also modulated the activation of the central DSB signalling kinase, ATM, in response to these agents. These effects required the functionality of the Mre11-Nbs1-Rad50 (MRN) complex and were mimicked by the inhibition of PP2A phosphatase. Therefore, tungstate may have adjuvant activity when combined with DNA-damaging agents in the treatment of several malignancies.

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Section: Discussionmentioning

confidence: 99%

Sodium tungstate modulates ATM function upon DNA damage

et al. 2013

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“…Furthermore, ATLD cells display normal activation of the ATM/CHK2/CDC25A pathway after exposure to ionizing radiation (Falck et al, 2002), suggesting that hMre11 may be involved only in the ATM/NBS1/ SMC1 pathway for intra-S phase checkpoint control, as observed in NBS cells. In contrast to the observation in vertebrates, yeast Mre11-mutant cells display defects in phosphorylation of yRad53 (the yeast homolog of CHK2) after treatment with bleomycin and hydroxyurea and hence, yeast intra-S phase checkpoint could be regulated by Mec1/yRad53 (ATR/CHK2 homologs) pathway (Grenon et al, 2001;D'Amours and Jackson, 2001).…”

Section: Nbs1 In Cell-cycle Checkpoint Controlmentioning

confidence: 99%

Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

et al. 2002

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DNA double-strand breaks represent the most potentially serious damage to a genome and hence, at least two pathways of DNA repair have evolved; namely, homologous recombination repair and non-homologous end joining. Defects in both rejoining processes result in genomic instability including chromosome rearrangements, LOH and gene mutations, which may lead to development of malignancies. Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation that induces double-strand breaks, and high frequency of malignancies. NBS1, the product of the gene underlying the disease, forms a multimeric complex with hMRE11/ hRAD50 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphorylated histone H2AX. The combination of the highlyconserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. This process collaborates with cell-cycle checkpoints at S and G2 phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance and DNA replication. Based on recent knowledge regarding NBS1, we propose here a two-step binding mechanism for damage recognition by repair proteins, and describe the molecular links to factors for genome stability.

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“…14). Without resection, mre11Δ G2-arrested cells also fail to activate the DNA damage checkpoint 15 (Fig. 3c).…”

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confidence: 99%

“…Because Mre11 is required for DSB resection and checkpoint activation 1,15,16 , we asked whether defective resection caused by CDK1 inactivation reflects the inability to load Mre11 on broken chromosomes. We found Mre11 at DSBs in G2 cells ( Fig.…”

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DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1

Ira

Pellicioli

Balijja

et al. 2004

Nature

651

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A single double-strand break (DSB) induced by HO endonuclease triggers both repair by homologous recombination and activation of the Mec1-dependent DNA damage checkpoint in budding yeast [1][2][3][4][5][6] . Here we report that DNA damage checkpoint activation by a DSB requires the cyclin-dependent kinase CDK1 (Cdc28) in budding yeast. CDK1 is also required for DSB-induced homologous recombination at any cell cycle stage. Inhibition of homologous recombination by using an analogue-sensitive CDK1 protein 7,8 results in a compensatory increase in nonhomologous end joining. CDK1 is required for efficient 5′ to 3′ resection of DSB ends and for the recruitment of both the single-stranded DNA-binding complex, RPA, and the Rad51 recombination protein. In contrast, Mre11 protein, part of the MRX complex, accumulates at unresected DSB ends. CDK1 is not required when the DNA damage checkpoint is initiated by lesions that are processed by nucleotide excision repair. Maintenance of the DSB-induced checkpoint requires continuing CDK1 activity that ensures continuing end resection. CDK1 is also important for a later step in homologous recombination, after strand invasion and before the initiation of new DNA synthesis.In budding yeast, a chromosomal DSB created by HO endonuclease has been used both to study the kinetics and efficiency of DSB repair and to analyse the induction of the DNA damage checkpoint dependent on Mec1 (an ATR homologue). In cells carrying HML or HMR mating-type switching donor sequences, a DSB at the MAT locus is efficiently repaired by gene conversion. In strains lacking donor sequences, induction of an unrepairable DSB causes arrest of cell cycle progression before anaphase 1,2 . In bothCorrespondence and requests for materials should be addressed to M.F. (marco.foiani@ifom-ieo-campus.it) or J.E.H. † Present address: Rockefeller University, 1230 York Avenue, New York, New York 10021-6399, USA. ★ These authors contributed equally to this work Supplementary Information accompanies the paper on www.nature.com/nature. Competing interests statementThe authors declare that they have no competing financial interests. instances, a key step is the 5′ to 3′ resection of DSB ends to produce single-stranded DNA (ssDNA), which is bound by the RPA complex. RPA binding is essential both for association of Mec1 checkpoint kinase 9 and for loading of Rad51 recombination protein 6 . HHS Public AccessActivation of the Mec1-dependent DNA damage checkpoint after a DSB is regulated by the cell cycle 3 , with no activation in G1-arrested cells. A DSB induced in cells that have been arrested in G1, and then released into S phase, results in hyperphosphorylation of the Mec1 target Rad53 after the completion of S phase, in G2 ( Supplementary Fig. S1a). To test whether the checkpoint depends on the activity of cyclin-dependent kinases, we inactivated CDK1 in nocodazole-blocked G2 cells. We overexpressed the CDK1/Clb inhibitor, Sic1 (ref. 10), in G2 cells at the same time that an unrepairable DSB was induced at MAT. CDK1 i...

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Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex

Cited by 166 publications

References 28 publications

Sodium tungstate modulates ATM function upon DNA damage

Sodium tungstate modulates ATM function upon DNA damage

Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1

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