TheRAD52epistasis group in mammalian double strand break repair

Petrini, John H.J.; Bressan, Debra A.; Yao, Ming

doi:10.1006/smim.1997.0067

Cited by 91 publications

(53 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The genetic analysis of the repair of DSBs indicates that it involves recombinational processes. While DSBs can be repaired by homologous recombination in an error-free manner in yeast (Petrini et al, 1997), this mechanism is apparently uncommon in mammalian cells and most DSBs appear to be repaired by an illegitimate recombination process that is error-prone and thus likely accounts for many of the potentially mutagenic DNA lesions induced by radiation. This process of non-homologous end rejoining involves protein complexes, such as the well-characterized DNA ± PK complex, the kinase activity being dependent upon the binding of the Ku protein to the broken DNA ends (Singleton et al, 1999), or the one which includes hRad50 and hMre11 (Carney et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

et al. 2002

View full text Add to dashboard Cite

is an error-prone enzyme which has been found to be overexpressed in several human tumors. By using a couple of recombinant CHO cells di ering only from the exogenous expression of Pol b b, we showed here that cells overexpressing Pol b b are much more sensitive to IR treatments by increasing apoptosis. We also found that the surviving cells displayed an hypermutator phenotype which could be explained by di erent pathways involving Pol b b, such as (i) an increased capacity to incorporate into DNA the mutagenic dGTP analog, 8-oxo-dGTP, one of the most abundant purine-derived nucleotides exposed to g girradiation, (ii) the induction of IR-induced DNA breaks and (iii) accumulation of chromosome aberrations induced by radiation. Alteration of Pol b b expression in irradiated cells thus appears to strengthen both cell death and genetic changes associated with a malignant phenotype. These data provide new insights into the cellular response to radiations and the associated carcinogenic consequences.

show abstract

Section: Discussionmentioning

confidence: 99%

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

et al. 2002

View full text Add to dashboard Cite

show abstract

“…HRR utilizes extensive homology to faithfully restore the DNA sequence around the DSB either by gene conversion or, less frequently, by the non-conservative process of single-strand annealing Haber, 1992;Kanaar et al, 1998;Petes et al, 1991;Petrini et al, 1997;Resnick, 1976;Shinohara and Ogawa, 1995;Szostak et al, 1983;Thacker, 1999;Thompson and Schild, 1999). NHEJ directly rejoins the two ends of the DNA molecule at the site of the DNA DSB without any requirement for homologous DNA sequences, and without necessarily restoring the sequence around the DSB (Jackson and Jeggo, 1995;Jeggo, 1998;Lieber et al, 1997;Weaver, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…NHEJ directly rejoins the two ends of the DNA molecule at the site of the DNA DSB without any requirement for homologous DNA sequences, and without necessarily restoring the sequence around the DSB (Jackson and Jeggo, 1995;Jeggo, 1998;Lieber et al, 1997;Weaver, 1996). There are striking similarities in the molecular mechanism of HRR and NHEJ between higher and lower eukaryotes, and several homologues of the RAD52 epistasis group of genes have been cloned in mammalian cells and shown to have biochemical functions similar to those determined in yeast Kanaar et al, 1998;Petrini et al, 1997;Shinohara and Ogawa, 1995;Thacker, 1999;Thompson and Schild, 1999). Also, genes implicated in NHEJ in mammalian cells such as KU, and DNA ligase IV have been found in yeast and shown to function similarly Jackson, 1996a,b, 1998;Grawunder et al, 1998a,b;Siede et al, 1996;Teo and Jackson, 1997).…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…The ScRad52 protein alone or a heterodimer of ScRad55 and ScRad57 functions as a cofactor in this reaction, probably by overcoming the inhibitory effect of replication protein A (32,45,49,50). Recently, ScRad54 has been shown to stimulate the pairing reaction (36).Homologues of most of the RAD52 group genes in S. cerevisiae have been identified in other yeast strains as well as in higher eukaryotes (1,15,26,30,35,53). As in yeast, physical interactions between HsRad51 and HsRad52 and between HsRad51 and HsRad54 proteins have been observed in mammals (17, 42).…”

mentioning

confidence: 99%

Targeted Inactivation of Mouse RAD52Reduces Homologous Recombination but Not Resistance to Ionizing Radiation

Rijkers

Ouweland

Morolli

et al. 1998

Molecular and Cellular Biology

302

243

View full text Add to dashboard Cite

The RAD52 epistasis group is required for recombinational repair of double-strand breaks (DSBs) and shows strong evolutionary conservation. In Saccharomyces cerevisiae, RAD52 is one of the key members in this pathway. Strains with mutations in this gene show strong hypersensitivity to DNA-damaging agents and defects in recombination. Inactivation of the mouse homologue of RAD52 in embryonic stem (ES) cells resulted in a reduced frequency of homologous recombination. Unlike the yeast Scrad52 mutant, MmRAD52 ؊/؊ ES cells were not hypersensitive to agents that induce DSBs. MmRAD52 null mutant mice showed no abnormalities in viability, fertility, and the immune system. These results show that, as in S. cerevisiae, MmRAD52 is involved in recombination, although the repair of DNA damage is not affected upon inactivation, indicating that MmRAD52 may be involved in certain types of DSB repair processes and not in others. The effect of inactivating MmRAD52 suggests the presence of genes functionally related to MmRAD52, which can partly compensate for the absence of MmRad52 protein.Double-strand breaks (DSBs) in the DNA of living organisms occur during several physiological processes including meiotic recombination, mating-type switching in yeast, and V(D)J rearrangement in developing B and T lymphocytes. Agents such as ionizing radiation and certain chemicals also lead to the induction of DSBs in the genome. If left unrepaired, DSBs result in broken chromosomes and cell death, as has been shown convincingly in yeast (5). Alternatively, incorrect repair of DSBs may generate deletions, chromosome rearrangements, and cell transformation and eventually lead to the formation of tumors.Two main pathways are known to be involved in the repair of DSBs in eukaryotes: end-to-end rejoining, a homology-independent but error-prone process, and error-free repair via (homologous) recombination. Repair of DSBs in the yeast Saccharomyces cerevisiae occurs predominantly via recombination, whereas a contribution of end-to-end rejoining can be observed only in a recombination-deficient background (9, 27, 47). Recombinational repair in S. cerevisiae involves the genes of the RAD52 epistasis group, of which nine members have been identified thus far (ScRAD50, ScRAD51, ScRAD52, ScRAD54, ScRAD55, ScRAD57, ScRAD59, ScMRE11, and ScXRS2) (2,11,15,16,44). Interestingly, it has been shown that ScRAD50, ScMRE11, and ScXRS2 are also involved in end-to-end rejoining (10,28,55). Mutations in genes of the RAD52 group result in an increased sensitivity to ionizing radiation and defects in one or more types of recombination. Among these mutants, the Scrad51, Scrad52, and Scrad54 mutants display the most severe radiation sensitivity and defects in recombination.Biochemical experiments with S. cerevisiae have shown that the ScRad51 protein forms nucleoprotein filaments with single-stranded DNA and promotes pairing and limited strand exchange (51). The ScRad52 protein alone or a heterodimer of ScRad55 and ScRad57 functions as a cofactor in this reaction, ...

show abstract

TheRAD52epistasis group in mammalian double strand break repair

Cited by 91 publications

References 0 publications

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

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

Targeted Inactivation of Mouse RAD52Reduces Homologous Recombination but Not Resistance to Ionizing Radiation

Contact Info

Product

Resources

About