XRCC3 deficiency results in a defect in recombination and increased endoreduplication in human cells

Yoshihara, Takashi; Ishida, Mari; Kinomura, Aiko; Katsura, Mari; Tsuruga, Takanori; Tashiro, Satoshi; Asahara, Toshimasa; Miyagawa, Kiyoshi

doi:10.1038/sj.emboj.7600087

Cited by 74 publications

(82 citation statements)

References 55 publications

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“…In contrast, depletion of XRCC3 transcription by siRNA in MCF7 cells inhibited cell proliferation, led to accumulation of DNA breaks and triggered activation of the p53-dependant cell death (40). XRCC3 deficient HCT116 cells have shown increased sensitivity to cisplatin and mitomycin C (42). Although some studies have shown no association between polymorphisms in XRCC3 and colorectal cancer risk (43)(44)(45)(46) other studies have (47,48), and in addition XRCC3 polymorphisms have also been associated with breast and lung cancer susceptibility (41,49).…”

Section: Discussionmentioning

confidence: 99%

Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line

Nicholl¹

2010

Oncol Rep

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Abstract. Regular aspirin intake is associated with a reduction in the incidence of colorectal cancer. Aspirin has been shown to be cytotoxic to colorectal cancer cells in vitro. The molecular basis for this cytotoxicity is controversial, with a number of competing hypotheses in circulation. One suggestion is that the protective effect is related to the induction of expression of the DNA mismatch repair (MMR) proteins hMLH1, hMSH2, hMSH6 and hPMS2 in DNA MMR proficient cells. We report that treatment of the DNA MMR competent/p53 mutant colorectal cancer cell line SW480 with 1 mM aspirin for 48 h caused changes in mRNA expression of several key genes involved in DNA damage signalling pathways, including a significant down-regulation in transcription of the genes ATR, BRCA1 and MAPK12. Increases in the transcription of XRCC3 and GADD45· genes are also reported. Regulation of these genes could potentially have profound effects on colorectal cancer cells and may play a role in the observed chemoprotective effect of aspirin in vivo. Although a correlation was not seen between transcript and protein levels of ATR, BRCA1 and GADD45·, an increase in XRCC3 encoded protein expression upon aspirin treatment in SW480 cells was observed by immunoblotting, immunofluorescence and immunohistochemical analysis. This is the first report of XRCC3 gene transcription and encoded protein expression being susceptible to exposure to the non-steroidal anti-inflammatory drug, aspirin. Furthermore, this study indicates that alterations in gene transcription seen in microarray studies must be verified at the protein level.

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Section: Discussionmentioning

confidence: 99%

Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line

Nicholl¹

2010

Oncol Rep

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“…Although these findings might suggest that the LOH mechanism in spontaneous tumors can be influenced by Rad54 inactivation, the sample size was too small to justify any mechanistic hypothesis. However, increased frequency of aneuplody, related to centrosome abnormalities, has also been observed in cells defective for other recombination genes such as BRCA1, BRCA2, XRCC2, XRCC3 and Rad51 paralogue family (Tutt et al, 1999;Xu et al, 1999;Griffin et al, 2000;Deans et al, 2003;Yoshihara et al, 2004;Smiraldo et al, 2005).…”

Section: Effect Of Rad54 and Dnapkcs Deficiency On Ptc1 Loh In Full-bmentioning

confidence: 99%

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

et al. 2011

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Heterozygous Patched1 (Ptc1 þ /À ) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1 þ /À mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1 þ / À mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.

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“…Our results show that the Rad51C-deficient HeLa cells display ϳ2-fold greater sensitivity to MMC using acute treatment, demonstrating that these cells have a similar phenotype for MMC sensitivity to that of the chicken and hamster mutants. An XRCC3 gene knockout in the human colon cancer cell line HCT116 has been reported recently, and the XRCC3-deficient cells showed ϳ2-fold excess sensitivity to MMC (58 (59,60) that is associated primarily with the late S/G 2 phase (49). By contrast, the NHEJ-defective Chinese hamster ovary mutants for XRCC4, Ku86, and DNA-PKcs (the XR-1, xrs5/6, and V3 cell lines, respectively) are highly sensitive to IR in G 1 and early S phases compared with the wild type but are more IR-resistant in late S/G 2 (61)(62)(63)(64).…”

Section: Rad51c Dynamically Influences the Protein Levels Of Other Rad51mentioning

confidence: 99%

Human Rad51C Deficiency Destabilizes XRCC3, Impairs Recombination, and Radiosensitizes S/G2-phase Cells

Lio

Schild

Brenneman

et al. 2004

Journal of Biological Chemistry

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The highly conserved Rad51 protein plays an essential role in repairing DNA damage through homologous recombination. In vertebrates, five Rad51 paralogs (Rad51B, Rad51C, Rad51D, XRCC2, and XRCC3) are expressed in mitotically growing cells and are thought to play mediating roles in homologous recombination, although their precise functions remain unclear. Among the five paralogs, Rad51C was found to be a central component present in two complexes, Rad51C-XRCC3 and Rad51B-Rad51C-Rad51D-XRCC2. We have shown previously that the human Rad51C protein exhibits three biochemical activities, including DNA binding, ATPase, and DNA duplex separation. Here we report the use of RNA interference to deplete expression of Rad51C protein in human HT1080 and HeLa cells. In HT1080 cells, depletion of Rad51C by small interfering RNA caused a significant reduction of frequency in homologous recombination. The level of XRCC3 protein was also sharply reduced in Rad51C-depleted HeLa cells, suggesting that XRCC3 is dependent for its stability upon heterodimerization with Rad51C. In addition, Rad51C-depleted HeLa cells showed hypersensitivity to the DNA-cross-linking agent mitomycin C and moderately increased sensitivity to ionizing radiation. Importantly, the radiosensitivity of Rad51C-deficient HeLa cells was evident in S and G 2 /M phases of the cell cycle but not in G 1 phase. Together, these results provide direct cellular evidence for the function of human Rad51C in homologous recombinational repair.In mammalian cells, DNA double strand breaks (DSBs) 1 are repaired primarily by two distinct mechanisms, non-homologous end joining (NHEJ), a non-templated, potentially errorprone process in which nucleotide alternations are tolerated at the site of rejoining, and homologous recombination (HR), a largely error-free process in which a sister chromatid or homologous chromosome is used as a template for repair (for review, see Refs. 1 and 2). Homologous recombinational repair (HRR) provides high fidelity in repairing DNA damage and is therefore essential and critical for the maintenance of genome stability and tumor avoidance (for review, see Refs. 3 and 4). The Rad51 protein plays a key role in HR, functioning to mediate homologous DNA pairing and strand exchange (5, 6). Five vertebrate Rad51 paralogs are expressed in mitotically growing cells: Rad51B (7-9), Rad51C (10), Rad51D (9, 11, 12), XRCC2 (13-15), and XRCC3 (13,16,17). These proteins share 20 -30% sequence identity with Rad51 and with each other. Only vertebrates appear to contain all five of these Rad51 paralogs. In human cells, Rad51C participates in various paralog complexes, including Rad51B-Rad51C, Rad51C-XRCC3, and Rad51B-Rad51C-Rad51D-XRCC2 (18 -22). In terms of proteinprotein interactions, Rad51C apparently has a central role, interacting directly with Rad51B, Rad51D, and XRCC3 and also weakly with Rad51 (23,24). However, the functional significance of these complexes is not yet clear.Mutant studies provide a direct means for identifying the function of genes. A knock-out ...

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XRCC3 deficiency results in a defect in recombination and increased endoreduplication in human cells

Cited by 74 publications

References 55 publications

Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line

Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

Human Rad51C Deficiency Destabilizes XRCC3, Impairs Recombination, and Radiosensitizes S/G2-phase Cells

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