Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase

Auclair, Yannick; Rouget, Raphael; Bélisle, Jonathan M.; Costantino, Santiago; Drobetsky, Elliot

doi:10.1016/j.dnarep.2010.03.013

Cited by 30 publications

(31 citation statements)

References 54 publications

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“…As mentioned earlier, we previously showed that cells deficient in DNA pol are profoundly defective in SPR (15). XP30ROsv is an SV40-transformed fibroblast cell line derived from an XPV pol-deficient patient; moreover, as expected, inhibition of 6-4PP repair during S phase is significantly rescued in this strain when engineered to re-express pol (XP30ROsv-clone 6; Fig.…”

Section: Spr Defects Correlate With Elevated Frequencies Of Spontaneomentioning

confidence: 99%

“…We previously demonstrated that deficiency in either ATR kinase (required for stabilization and restart of stalled replication forks post-UV) or DNA pol (required for efficient bypass of replication-blocking UV-induced DNA adducts) generates profound defects in NER exclusively during S phase (13)(14)(15). To probe the mechanistic basis for this phenomenon, we exploited the powerful experimental model provided by the budding yeast S. cerevisiae.…”

Section: Discussionmentioning

confidence: 99%

“…Partial Depletion of Rfa1 Inhibits SPR-We originally speculated (15), and more recently others have presented evidence supporting the notion (17), that abnormal accumulation of RPA1-3 at damaged DNA replication forks could reduce the availability of this complex for NER during S phase. To directly test this model in yeast, we investigated the effect of partial RPA depletion on CPD removal in replicating cells.…”

Section: Spr Defects Correlate With Elevated Frequencies Of Spontaneomentioning

confidence: 99%

“…However, one potential connection relates to the fact that cells derived from pol-deficient skin cancer-prone xeroderma pigmentosum variant (XPV) patients or from ATR-deficient Seckel syndrome patients each exhibit increased replication fork stalling in response to UV (18,19). Based on this, we (15) and others (17) have postulated a functional link between levels of replicative stress and NER efficiency.…”

mentioning

confidence: 99%

“…We also reported that inactivating mutations in POLH, encoding translesion DNA polymerase (pol), cause a similarly striking cell cyclespecific repair defect (15). Pol is normally required to forestall mutagenesis in UV-irradiated cells via its capacity to perform relatively error-free replicative bypass of CPDs (16).…”

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confidence: 99%

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Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Bart

Angers

Fortier

et al. 2016

Journal of Biological Chemistry

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Nucleotide excision repair (NER) is a highly conserved pathway that removes helix-distorting DNA lesions induced by a plethora of mutagens, including UV light. Our laboratory previously demonstrated that human cells deficient in either ATM and Rad3-related (ATR) kinase or translesion DNA polymerase (i.e. key proteins that promote the completion of DNA replication in response to UV-induced replicative stress) are characterized by profound inhibition of NER exclusively during S phase. Toward elucidating the mechanistic basis of this phenomenon, we developed a novel assay to quantify NER kinetics as a function of cell cycle in the model organism Saccharomyces cerevisiae. Using this assay, we demonstrate that in yeast, deficiency of the ATR homologue Mec1 or of any among several other proteins involved in the cellular response to replicative stress significantly abrogates NER uniquely during S phase. Moreover, initiation of DNA replication is required for manifestation of this defect, and S phase NER proficiency is correlated with the capacity of individual mutants to respond to replicative stress. Importantly, we demonstrate that partial depletion of Rfa1 recapitulates defective S phase-specific NER in wild type yeast; moreover, ectopic RPA1-3 overexpression rescues such deficiency in either ATR-or polymerase -deficient human cells. Our results strongly suggest that reduction of NER capacity during periods of enhanced replicative stress, ostensibly caused by inordinate sequestration of RPA at stalled DNA replication forks, represents a conserved feature of the multifaceted eukaryotic DNA damage response.

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Section: Spr Defects Correlate With Elevated Frequencies Of Spontaneomentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Spr Defects Correlate With Elevated Frequencies Of Spontaneomentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Bart

Angers

Fortier

et al. 2016

Journal of Biological Chemistry

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Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation

Musich

Zou

2017

Advances in Experimental Medicine and Biology

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The sensitivity of Xeroderma pigmentosa (XP) patients to sunlight has spurred the discovery and genetic and biochemical analysis of the eight XP gene products (XPA-XPG plus XPV) responsible for this disorder. These studies also have served to elucidate the nucleotide excision repair (NER) process, especially the critical role played by the XPA protein. More recent studies have shown that NER also involves numerous other proteins normally employed in DNA metabolism and cell cycle regulation. Central among these is ataxia telangiectasia and Rad3-related (ATR), a protein kinase involved in intracellular signaling in response to DNA damage, especially DNA damage-induced replicative stresses. This review summarizes recent findings on the interplay between ATR as a DNA damage signaling kinase and as a novel ligand for intrinsic cell death proteins to delay damage-induced apoptosis, and on ATR's regulation of XPA and the NER process for repair of UV-induced DNA adducts. ATR's regulatory role in the cytosolic-to-nuclear translocation of XPA will be discussed. In addition, recent findings elucidating a non-NER role for XPA in DNA metabolism and genome stabilization at ds-ssDNA junctions, as exemplified in prematurely aging progeroid cells, also will be reviewed.

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Both XPA and DNA polymerase eta are necessary for the repair of doxorubicin-induced DNA lesions

et al. 2012

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Doxorubicin (DOX) is an important tumor chemotherapeutic agent, acting mainly by genotoxic action. This work focus on cell processes that help cell survival, after DOX-induced DNA damage. In fact, cells deficient for XPA or DNA polymerase eta (pol eta, XPV) proteins (involved in distinct DNA repair pathways) are highly DOX-sensitive. Moreover, LY294002, an inhibitor of PIKK kinases, showed a synergistic killing effect in cells deficient in these proteins, with a strong induction of G2/M cell cycle arrest. Taken together, these results indicate that XPA and pol eta proteins participate in cell resistance to DOX-treatment, and kinase inhibitors can selectively enhance its killing effects, probably reducing the cell ability to recover from breaks induced in DNA.

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Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase

Cited by 30 publications

References 54 publications

Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation

Both XPA and DNA polymerase eta are necessary for the repair of doxorubicin-induced DNA lesions

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