Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair
Open accessAbstract
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 η (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 η-deficient human cells. Our results strongly suggest that reduction of NER capacity during periods of enhanced replicative stress, ostensibly caused by inordinate seque…
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Such S phase NER defects can be caused by abnormal replicative stress responses, leading to excessive sequestration of heterotrimeric RPA in trans at persistently stalled replication forks or aberrantly activated origins of replication, which prevents RPA's essential action in NER.
“we and others previously demonstrated that such defects can be caused by abnormal replicative stress responses (e.g., in ATR- and pol eta-deficient cells), leading to excessive sequestration of heterotrimeric RPA in trans at persistently stalled replication forks or aberrantly activated origins of replication, which in turn prevents the essential action of this complex in NER (10, 11, 14).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [10]
Upon severe UV-induced replication stress, excessive sequestration of RPA on ssDNA located at persistently stalled replication forks, or at aberrantly activated origins of replication, limits the availability of this complex to act in NER during S phase.
“Upon severe UV-induced replication stress, excessive sequestration of RPA on ssDNA located at persistently stalled replication forks, or at aberrantly activated origins of replication, was shown by our group and others to limit the availability of this complex to act in NER during S phase (10, 11, 14).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [10]
Defective responses to DNA replication stress, for example, in cells depleted for ATR or pol eta, cause striking GG-NER defects during S phase, whereas repair in G1 or G2/M is not significantly impacted.
“We previously demonstrated that defective responses to DNA replication stress, for example, in cells depleted for ataxia telangiectasia and rad 3-related kinase (ATR) or translesion DNA polymerase eta (pol eta), cause striking GG-NER defects during S phase, whereas repair in G1 or G2/M is not significantly impacted (GG-NER during S phase is hereafter denoted S phase NER) (8, 9, 10, 11).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [10]
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Understanding nucleotide excision repair and its roles in cancer and ageing
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Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR
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Shining a light on xeroderma pigmentosum
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Self-citationTaschner, M., Harreman, M., Teng, Y., Gill, H., Anindya, R., Maslen, S. L., Skehel, J. M., Waters, R., & Svejstrup, J. Q. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00822-09 · Cited by 19 · cited 3× · see citing works
“reflecting inhibition of both TC-NER and GG-NER, respectively) (20).”
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Roles of UVA radiation and DNA damage responses in melanoma pathogenesis
Khan, A. Q., Travers, J. B., & Kemp, M. G. (2018) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22176 · Cited by 152 · see citing works
Bélanger, F., Fortier, E., Dubé, M., Lemay, J.-F., Buisson, R., Masson, J.-Y., Elsherbiny, A., Costantino, S., Carmona, E., Mes-Masson, A.-M., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0618 · Cited by 58 · see citing works
Self-citationBélanger, F., Roussel, C., Sawchyn, C., St-Hilaire, E., Gezzar-Dandashi, S., Kimenyi Ishimwe, A. B., Mallette, F. A., Wurtele, H., & Drobetsky, E. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104900 · Cited by 9 · see citing works
Self-citation
- Authors
- Bélanger, F., Angers, J.-P., Fortier, É., Hammond-Martel, I., Costantino, S., Drobetsky, E., & Wurtele, H.
- Affiliations
- Hôpital Maisonneuve-Rosemont (CA)
- Corresponding author
- Drobetsky, Elliot
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 291
- Issue
- 2
- Pages
- 522-537
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4705374
- OpenAlex
- W2229939127
- Cited by
- 24
- References
- 7
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 3 · 2022: 5 · 2020: 1 · 2019: 6 · 2018: 3 · 2017: 3
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-123438, MOP-133470)
- Natural Sciences and Engineering Research Council of Canada (RGPIN 435636–2013, RGPIN-2014–05285, RGPIN 355603–2011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- nucleotide excision repair, S phase, replicative stress, RPA, Rfa1, DNA damage response, DNA replication initiation, UV-induced DNA damage, Saccharomyces cerevisiae, DNA repair kinetics
- MeSH terms
- DNA Repair, Humans, Mutagens, Mutation, Phosphorylation, Pyrimidine Dimers, Saccharomyces cerevisiae, Stress, Physiological, S Phase, Saccharomyces cerevisiae Proteins, Cell Line, Tumor, Replication Protein A
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