Interplay between human DNA repair proteins at a unique double-strand break in vivo

Rodrigue, Amélie; Lafrance, Matthieu; Gauthier, Marie-Christine; McDonald, Darin; Hendzel, Michael J.; West, Stephen C.; Jasin, Maria; Masson, Jean‐Yves

doi:10.1038/sj.emboj.7600914

Cited by 177 publications

(191 citation statements)

References 43 publications

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“…This raises the question of the fate of DNA ends generated in G1, during S phase ( Figure 6a). As KU86/KU70 can efficiently bind to DSBs in G1 (Rodrigue et al, 2006) it should be able to protect the ends. In addition, various other proteins such as g-H2AX, 53BP1 and RAD50/MRE11/NBS1 are good candidates for protection of DNA ends, allowing DSBs to progress through S phase.…”

Section: Discussionmentioning

confidence: 99%

“…In the present data, if unrepaired DSBs can progress through S phase, DSBs should be present on both chromatids at the same locus Figure 6 Unrepaired DSBs produced in the G1 phase. (a) Potential successive processing steps of unrepaired DSBs in G1: KU80/ KU70 can efficiently bind to the DNA in the G1 phase (Rodrigue et al, 2006) and can protect the DNA ends against extensive degradation. If the G1 checkpoint is inefficient, cells with unrepaired DSBs can progress through cell cycle.…”

Section: Impact On Genome Stability Maintenancementioning

confidence: 99%

“…This is due to the fact that a large majority of NHEJ-defective cells are hypersensitive to IR when irradiated in G1 but not in G2 (Stamato et al, 1988;Jeggo, 1990;Lee et al, 1997;Takata et al, 1998;Wang et al, 2001). Recently, this interpretation found molecular support by data showing that KU80 preferentially binds to DSBs in the G1 phase (Rodrigue et al, 2006). However, this view is challenged by the fact that NHEJ has been proposed to act in S phase (Saintigny et al, 2001;Mills et al, 2004) and throughout the cell cycle (Rothkamm et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

et al. 2006

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Non-homologous end joining (NHEJ) and homologous recombination (HR) are two pathways that can compete or cooperate for DNA double-strand break (DSB) repair. NHEJ was previously shown to act throughout the cell cycle whereas HR is restricted to late S/G2. Paradoxically, we show here that defect in XRCC4 (NHEJ) leads to over-stimulation of HR when cells were irradiated in G1, not in G2. However, XRCC4 defect did not modify the strict cell cycle regulation for HR (i.e. in S/G2) as attested by (i) the formation of Rad51 foci in late S/G2 whatever the XRCC4 status, and (ii) the fact that neither Rad51 foci nor HR (gene conversion plus single-strand annealing) events induced by ionizing radiation were detected when cells were maintained blocked in G1. Finally, both c-H2AX analysis and pulse field gel electrophoresis showed that following irradiation in G1, some DSBs reached S/G2 in NHEJ-defective cells. Taken together, our results show that when cells are defective in G1/S arrest, DSB produced in G1 and left unrepaired by XRCC4 can be processed by HR but in late S/G2.

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Section: Discussionmentioning

confidence: 99%

Section: Impact On Genome Stability Maintenancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

et al. 2006

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“…Recruitment of HR proteins Rad51 and Rad52 only occurs when Mre11 and Tel1 foci disassemble. IScel cleavage has also been utilized in human cells to demonstrate recruitment of Mre11 and other repair proteins to the cleavage site (Rodrigue et al, 2006). To understand the roles of ATM and Nbs1 in chromatin structure modulation at a specific DNA DSB, Berkovich et al (2007) used the eukaryotic homing endonuclease I-Ppol (15-bp recognition sequence) to cleave DNA at endogenous target sites in the human genome.…”

Section: Viral Infection and In Vitro Models To Investigate The Rolementioning

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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“…Subsequently, the RAD51-bound single-stranded DNA invades a homologous molecule in a reaction stimulated by RAD54. This invasion leads to Holliday junction formation which is thought to be resolved by a complex containing XRCC3 and RAD51C [21][22].…”

Section: Introductionmentioning

confidence: 99%

Homologous recombination repair protects against particulate chromate-induced chromosome instability in Chinese hamster cells

Stackpole

Wise

Goodale

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Particulate hexavalent chromium [Cr(VI)] compounds are well-established human carcinogens. Cr (VI)-induced tumors are characterized by chromosomal instability (CIN); however, the mechanisms of this effect are unknown. We investigated the hypothesis that homologous recombination (HR) repair of DNA double strand breaks protect cells from Cr(VI)-induced CIN by focusing on the XRCC3 and RAD51C genes, which play an important role in cellular resistance to DNA double strand breaks. We used Chinese hamster cells defective in each HR gene (irs3 for RAD51C and irs1SF for XRCC3) and compared with their wildtype parental and cDNA-complemented controls. We found that the intracellular Cr ion levels varied among the cell lines after particulate chromate treatment. Importantly, accounting for differences in Cr ion levels, we discovered that XRCC3 and RAD51C cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, relative to wild-type and cDNA-complimented cells. We also observed the emergence of high levels of chromatid exchanges in the two mutant cell lines. For example, 1 ug/cm 2 lead chromate induced 20 and 32 exchanges in XRCC3-and RAD51C-deficient cells, respectively, whereas no exchanges were detected in the wildtype and cDNA-complemented cells. These observations suggest that HR protects cells from Cr(VI)-induced CIN, consistent with the ability of particulate Cr(VI) to induce double strand breaks.

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Interplay between human DNA repair proteins at a unique double-strand break in vivo

Cited by 177 publications

References 43 publications

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

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

Homologous recombination repair protects against particulate chromate-induced chromosome instability in Chinese hamster cells

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