Review of repair kinetics for DNA damage induced in eukaryotic cells in vitro by ionizing radiation

Frankenberg-Schwager, M.

doi:10.1016/0167-8140(89)90143-6

Cited by 193 publications

(58 citation statements)

References 93 publications

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“…The nature of the slow component is not known, but it has been speculated that it re¯ects repair of DNA DSBs by HRR (Weibezahn and Coquerelle, 1981). Although this hypothesis is compatible with the slow kinetics expected for HRR (Frankenberg-Schwager, 1989;Friedberg et al, 1995), it is incompatible with the error-prone nature of the slow component (Loebrich et al, 1995), and the lack of defects in DNA DSB rejoining in XRCC2 and XRCC3 mutants (Cheong et al, 1992;Thacker and Ganesh, 1990;Thompson and Schild, 1999). We introduced, therefore, DT40 cells to systematically evaluate the contribution of HRR in DNA DSB rejoining.…”

Section: Resultsmentioning

confidence: 84%

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

et al. 2001

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Rejoining of ionizing radiation (IR) induced DNA DSBs usually follows biphasic kinetics with a fast (t 50 : 5 ± 30 min) component attributed to DNA-PK-dependent non-homologous endjoining (NHEJ) and a slow (t 50 : 1 ± 20 h), as of yet uncharacterized, component. To examine whether homologous recombination (HR) contributes to DNA DSB rejoining, a systematic genetic study was undertaken using the hyper-recombinogenic DT40 chicken cell line and a series of mutants defective in HR. We show that DT40 cells rejoin IR-induced DNA DSBs with half times of 13 min and 4.5 h and contributions by the fast (78%) and the slow (22%) components similar to those of other vertebrate cells with 1000-fold lower levels of HR. We also show that deletion of RAD51B, RAD52 and RAD54 leaves unchanged the rejoining half times and the contribution of the slow component, as does also a conditional knock out mutant of RAD51. A signi®cant reduction (to 37%) in the contribution of the fast component is observed in Ku70 7/7 DT40 cells, but the slow component, operating with a half time of 18.4 h, is still able to rejoin the majority (63%) of DSBs. A double mutant Ku70 7/7 /RAD54 7/7 shows similar half times to Ku70 7/7 cells. Thus, variations in HR by several orders of magnitude leave unchanged the kinetics of rejoining of DNA DSBs, and fail to modify the contribution of the slow component in a way compatible with a dependence on HR. We propose that, in contrast to yeast, cells of vertebrates are`hard-wired' in the utilization of NHEJ as the main pathway for rejoining of IR-induced DNA DSBs and speculate that the contribution of homologous recombination repair (HRR) is at a stage after the initial rejoining. Oncogene (2001) 20, 2212 ± 2224.

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Section: Resultsmentioning

confidence: 84%

“…The increase in FAR is initially linear with dose but bends downwards above 30 Gy. Because DSBs are induced linearly with IR dose (Frankenberg-Schwager, 1989;Iliakis, 1991), this bending, which re¯ects a change in the sensitivity of the assay, must be considered in the quantitative analysis of the repair data (Wachsberger et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2001

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“…However, under our experimental setting using alkaline condition, the BPDE-induced DNA adducts and oxidative damages can be converted into DNA strand breaks that are detectable using the alkaline comet assay [25,39,40]. Recognition and incision are the rate-limiting steps in NER while rejoining of DNA strand breaks is a rapid process with a halftime of a few minutes in most cell types [41]. DNA breaks are only transiently present in the NER process [42].…”

Section: Discussionmentioning

confidence: 93%

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

et al. 2008

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XPC, a key protein in the nucleotide excision repair (NER) pathway, recognizes damaged DNA and initiates NER. Genetic variations in the XPC gene might be associated with altered DNA repair capacities (DRC). In this study, we genotyped three XPC polymorphisms, Ala499Val (C→T), PAT (-/+) and Lys939Gln (A→C), and measured the DNA damage/DRC by alkaline comet assay challenged by BPDE and gamma-radiation in 476 healthy subjects. We also evaluated the associations between DNA damage/DRC and genotypes of XPC polymorphisms. Compared with the XPC Lys939Gln homozygous wild type (AA) subjects, subjects with the variant alleles (AC and CC) had significantly higher DNA damages induced by BPDE (Median and 95% confidence interval [CI]: 3.16 (3.01-3.44) vs. 2.88 (2.51-3.05), P=0.01), and gamma-radiation (4.18(3.94-4.44) vs. 3.71 (3.49-4.04), P=0.01). However, subjects with the variant alleles (CT and TT) of Ala499Val exhibited a 8.6 % and 13.1% decrease in DNA damages induced by BPDE (P=0.05) and gamma-radiation (P=0.001), respectively. Significant correlations were found between genotypes and induced DNA damages in XPC Lys939Gln (For BPDE: R=0.12, P=0.01; for gamma-radiation: R=0.094, P=0.046) and Ala499Val (For BPDE: R=-0.11, P=0.03; for gamma-radiation: R=-0.16, P=0.0009). The haplotypes "T-A" (in the order of Ala499Val-PAT-Lys939Gln) was associated with the lowest DNA damages. Our results suggested that the DRC of host cells might be modulated by specific XPC polymorphisms.

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“…A large amount of evidence indicates that unrepaired or misrepaired DSBs in the DNA can lead to cell death/ apoptosis (Ward, 1988;Frankenberg-Schwager, 1989;Iliakis, 1991;McMillan and Peacock, 1994;Jeggo, 1998). The death resulting from radiation is now, to a considerable degree, understood as radiosensitivity.…”

Section: P53-mediated Apoptosis In Irmentioning

confidence: 99%

P53 and radiation responses

2003

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Cells have evolved elaborate mechanisms (checkpoints) to monitor genomic integrity in order to ensure the highfidelity transmission of genetic information. Cells harboring defects in checkpoint pathways respond to DNA damage improperly, which in turn may enhance the rate of cancer development. Ionizing radiation (IR) primarily leads to double-strand DNA breaks (DSBs), which activate DNA damage checkpoints to initiate signals ultimately leading to a binary decision between cell death and cell survival. TP53 has been recognized as an important checkpoint protein, functioning mainly through transcriptional control of target genes that influence multiple response pathways and leading to the diversity of responses to IR in mammalian cells. We review how the tumor suppressor P53 is involved in the complex response to IR to enforce the cell's fate to live by inducing the growth arrest coupled to DNA damage repair or to die by inducing irreversible growth arrest or apoptosis. Moreover, recent insights have emerged in our understanding of how P53 modulates radiosensitivity in tissues following IR as well as its role in sensitizing cells to chemo-and radiotherapy. The P53 pathway remains an attractive target for exploitation in the war on cancer.

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Review of repair kinetics for DNA damage induced in eukaryotic cells in vitro by ionizing radiation

Cited by 193 publications

References 93 publications

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

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

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

P53 and radiation responses

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