Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes.

Haaf, Thomas; Golub, Efim I.; Reddy, Gurucharan; Radding, Charles M.; Ward, David C.

doi:10.1073/pnas.92.6.2298

Cited by 511 publications

(398 citation statements)

References 24 publications

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“…Similarly, RAD51 forms foci on meiotic chromosomes, where it colocalizes with DMC1 (Barlow et al, 1997;Tarsounas et al, 1999). These foci appear similar to the RAD51 foci observed in somatic cells after DNA damage and presumably identify sites of meiotic recombination (Haaf et al, 1995;Raderschall et al, 1999).…”

Section: Predominant In G1supporting

confidence: 54%

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BRCA2: a universal recombinase regulator

2007

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Homologous recombination has a dual role in eukaryotic organisms. Firstly, it is responsible for the creation of genetic variability during meiosis by directing the formation of reciprocal crossovers that result in random combinations of alleles and traits. Secondly, in mitotic cells, it maintains the integrity of the genome by promoting the faithful repair of DNA double-strand breaks (DSBs). In vertebrates, it therefore plays a key role in tumour avoidance. Mutations in the tumour suppressor protein BRCA2 are associated with predisposition to breast and ovarian cancers, and loss of BRCA2 function leads to genetic instability. BRCA2 protein interacts directly with the RAD51 recombinase and regulates recombinationmediated DSB repair, accounting for the high levels of spontaneous chromosomal aberrations seen in BRCA2-defective cells. Recent observations indicate that BRCA2 also plays a critical role in meiotic recombination, this time through direct interactions with the meiosis-specific recombinase DMC1. The interactions of BRCA2 with RAD51 and DMC1 lead us to suggest that the BRCA2 tumour suppressor is a universal regulator of recombinase actions.

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Section: Predominant In G1supporting

confidence: 54%

“…In undamaged cells, RAD51 is normally distributed throughout the nucleus, but during S phase or after treatment with DNA-damaging agents such as IR or mitomycin C, RAD51 forms distinct nuclear foci (Haaf et al, 1995;Scully et al, 1997). These foci are thought to represent sites on chromatin where DNA repair reactions take place.…”

Section: Predominant In G1mentioning

confidence: 99%

BRCA2: a universal recombinase regulator

2007

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“…IR-induced Rad51 foci assembly occurs in late S/G2 independently of NHEJ status After genotoxic stress, Rad51 assembles into nuclear foci at DNA damage sites, associated with g-H2AX-irradiated chromosome domains, and these are thus thought to represent recombination/repair centers (Haaf et al, 1995;Raderschall et al, 1999;Tashiro et al, 2000;Aten et al, 2004). In addition, Rad51 foci assembly seems to represent a pre-requisite as until now no HR events have been recorded when Rad51 assembly is impaired.…”

Section: Resultsmentioning

confidence: 99%

“…Following staining with the secondary antibody (Cyt2, Jackson ImmunoResearch Laboratories, Newmarket, Suffolk, England), the cells were analysed by epifluorescence microscopy. The Rad51 foci were analysed as described (Haaf et al, 1995) using anti-Rad51 antibody (Pharmingen, Le Pont-De-Claix, RA, France).…”

Section: Western Blot Analysismentioning

confidence: 99%

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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“…These foci are thought to correspond to Rad51 containing nucleoprotein filaments in the Dsb recombination process (Haaf et al, 1995;Yamamoto et al, 1996) and contain the ssDNA-binding replication protein A (RPA), Rad52 and Rad54 Gupta et al, 1998;Liu et al, 1999;Tan et al, 1999). Ionising-radiation-induced DNA damage increases the percentage of cells with Rad51 foci in a dose-and time-dependent manner, with a maximum at about 3 -6 h after irradiation (Bishop et al, 1998).…”

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confidence: 99%

Targeting of Rad51-dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines

et al. 2005

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The aim of the present work was to study the role of Rad51-dependent homologous recombination in the radiation response of non-small-cell lung cancer (NSCLC) cell lines. A dose-and time-dependent increase in the formation of Rad51 and g-H2AX foci with a maximum at about 4 and 1 h after irradiation, followed by a decrease, has been found. The relative fraction of cells with persisting Rad51 foci was 20 -30% in radioresistant and 60 -80% in radiosensitive cell lines. In comparison, a higher fraction of residual Dsb was evident in cell lines with nonfunctional p53. Transfection with As-Rad51 significantly downregulates radiation-induced formation of Rad51 foci and increases apoptosis, but did not influence the rejoining of DNA double-strand breaks. Interestingly, wortmannin, a well-known inhibitor of nonhomologous end-joining, also inhibits Rad51 foci formation. In general, there was no correlation between the clonogenic survival at 2 Gy and the percentage of initial Rad51 or g-H2AX foci after ionising radiation (IR). The most reliable predictive factor for radiosensitivity of NSCLC cell lines was the relative fraction of Rad51 foci remaining at 24 h after IR. Although most of the Rad51 foci are co-localised with g-H2AX foci, no correlation of the relative fraction of persisting g-H2AX foci and SF2 is evident.

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Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes.

Cited by 511 publications

References 24 publications

BRCA2: a universal recombinase regulator

BRCA2: a universal recombinase regulator

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

Targeting of Rad51-dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines

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