Efficient rejoining of radiation-induced DNA double-strand breaks in vertebrate cells deficient in genes of the RAD52 epistasis group

Wang, Huichen; Zeng, Zhao Chong; Bui, Tu Anh; Sonoda, Eiichiro; Takata, Minoru; Takeda, Shunichi; Iliakis, George

doi:10.1038/sj.onc.1204350

Cited by 147 publications

(106 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, no contribution of Rad51-dependent HR in the direct removal of radiation-induced Dsb as measured by the FAR assay is evident from these data. In this respect, Wang et al (2001) also have shown that HR did not measurably contribute to the removal of radiation-induced Dsb, even under conditions where NHEJ is compromised.…”

Section: -Test)mentioning

confidence: 81%

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

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Section: -Test)mentioning

confidence: 81%

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

et al. 2005

View full text Add to dashboard Cite

show abstract

“…This would be consistent with our data evidencing an apparently normal early DNA repair-associated disappearance of g-H2AX foci, regardless of Chk2 expression, at least after low-dose IR. Given the delay with which Chk2 is activated (relative to rapid activation of ATM), we cannot exclude that DSBs resistant to a first wave of repair activity (Nunez et al, 1995;Wang et al, 2001) could function as an activating signal for Chk2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks

et al. 2004

View full text Add to dashboard Cite

The diverse checkpoint responses to DNA damage may reflect differential sensitivities by molecular components of the damage-signalling network to the type and amount of lesions. Here, we determined the kinetics of activation of the checkpoint kinases ATM and Chk2 (the latter substrate of ATM) in relation to the initial yield of genomic DNA single-strand (SSBs) and double-strand breaks (DSBs). We show that doses of c-radiation (IR) as low as 0.25 Gy, which generate vast numbers of SSBs but only a few DSBs per cell (o8), promptly activate ATM kinase and induce the phosphorylation of the ATM substrates p53-Ser15, Nbs1-Ser343 and Chk2-Thr68. The full activation of Chk2 kinase, however, is triggered by treatments inflicting 419 DSBs per cell (e.g. 1 Gy), which cause Chk2 autophosphorylation on Thr387, Chk2-dependent accumulation of p21 waf1 and checkpoint arrest in the S phase. Our results indicate that, in contrast to ATM, Chk2 activity is triggered by a greater number of DSBs, implying that, below a certain threshold level of lesions (o19 DSBs), DNA repair can occur through ATM, without enforcing Chk2-dependent checkpoints.

show abstract

“…In DNA-PKcs de®cient cells, however, the contribution of the fast component is reduced without a measurable change in the half time, and the slow component, acting quasi as a backup, removes a substantially larger proportion of DNA DSBs (*70%). Interestingly, DNA DSB repair proceeds to similar ®nal levels in DNA-PKcs pro®cient and DNA-PKcs de®cient cells Nevaldine et al, 1997;Wang et al, 2000).…”

Section: Repair Inhibition In Caffeine Radiosensitizationmentioning

confidence: 99%

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

et al. 2000

Self Cite

View full text Add to dashboard Cite

The radiosensitizing e ect of ca eine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in ca eine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is a ected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays signi®cantly diminished ca eine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, ca eine e ectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not su cient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced ca eine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous endjoining (NHEJ) is radiosensitized by ca eine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly re¯ects NHEJ, remains una ected by ca eine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that ca eine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not su cient to explain radiosensitization. Indeed, immortalized ®bro-blasts from AT patients show ca eine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that ca eine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR. Oncogene (2000) 19, 5788 ± 5800.

show abstract

Efficient rejoining of radiation-induced DNA double-strand breaks in vertebrate cells deficient in genes of the RAD52 epistasis group

Cited by 147 publications

References 103 publications

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

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

Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

Contact Info

Product

Resources

About