A UVR-induced G2-phase checkpoint response to ssDNA gaps produced by replication fork bypass of unrepaired lesions is defective in melanoma
Open accessAbstract
UVR is a major environmental risk factor for the development of melanoma. Here we describe a coupled DNA-damage tolerance (DDT) mechanism and G2-phase cell cycle checkpoint induced in response to suberythemal doses of UVR that is commonly defective in melanomas. This coupled response is triggered by a small number of UVR-induced DNA lesions incurred during G1 phase that are not repaired by nucleotide excision repair (NER). These lesions are detected during S phase, but rather than stalling replication, they trigger the DDT-dependent formation of single-stranded DNA (ssDNA) gaps. The ssDNA attracts replication protein A (RPA), which initiates ATR-Chk1 (ataxia telangiectasia and Rad3-related/checkpoint kinase 1) G2-phase checkpoint signaling, and colocalizes with components of the RAD18 and RAD51 postreplication repair pathways. We demonstrate that depletion of RAD18 delays both the resolution of RPA foci and exit from the G2-phase arrest, indicating the involvement of RAD18-dependent postreplication repair in ssDNA gap repair during G2 phase. Moreover, the presence of RAD51 and BRCA1 suggests that an error-free mechanism may also contribute to repair. Loss of the UVR-induced G2-phase checkpoint results in increased UVR signature mutations after exposure to suberythemal UVR. We propose that defects in the UVR-induced G2-phase checkpoint and repair mechanism are likely to contribute to melanoma development.
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In UVC-irradiated XP-C cells, ATR activation might be triggered by accumulation of ssDNA gaps during replication, leading to mild and temporary G2-phase arrest.
“In UVC-irradiated XP-C cells, ATR activation might be triggered by the accumulation of ssDNA gaps during DNA replication, leading to a mild and temporary G2-phase arrest, in agreement with previous work [18,19,24,50]”
From Gap-filling and bypass at the replication fork are both active mechanisms for tolerance of low-dose ultraviolet-induced DNA damage in the human genome (2014) · cites this paper as [19]
If ssDNA gaps are left unfilled, checkpoint signals are activated and lead to G2-phase cell cycle arrest.
“If the ssDNA gaps are left unfilled, checkpoint signals are activated leading to a G2-phase cell cycle arrest [17][18][19].”
From Gap-filling and bypass at the replication fork are both active mechanisms for tolerance of low-dose ultraviolet-induced DNA damage in the human genome (2014) · cites this paper as [19]
UV exposure produced mutant colonies in all melanocyte cell lines tested, with mutation frequencies similar to other hprt mutagenesis studies.
“UV exposure resulted in mutant colony formation in all cell lines (Figure 4A), with similar mutation frequencies to other hprt mutagenesis studies”
From RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage (2014) · cites this paper as Wigan et al., 2012
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References 49 · Cited by 17
- Authors
- Wigan, M., Pinder, A., Giles, N., Pavey, S., Burgess, A., Wong, S., Sturm, R. A., & Gabrielli, B.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Gabrielli, Brian
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 132
- Issue
- 6
- Pages
- 1681-1688
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2084045125
- Cited by
- 17
- References
- 49
- Citations by year
- 2021: 1 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 1 · 2012: 1
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council
- Cancer Council Queensland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- ultraviolet radiation, melanoma, DNA damage tolerance, single-stranded DNA gaps, nucleotide excision repair, replication protein A, ATR-Chk1 signaling, RAD18, RAD51, BRCA1, postreplication repair, error-free repair, DNA repair deficiency
- MeSH terms
- Epidermal Cells, DNA Replication, DNA-Binding Proteins, DNA, Single-Stranded, Epidermis, Humans, Melanoma, Mutation, Skin Neoplasms, Ultraviolet Rays, G1 Phase, G2 Phase, S Phase, CDC2 Protein Kinase, Cell Line, Tumor, Cyclin B1, Cell Cycle Checkpoints
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