A UVR-Induced G2-Phase Checkpoint Response to ssDNA Gaps Produced by Replication Fork Bypass of Unrepaired Lesions Is Defective in Melanoma
| Autor: | Andrew Burgess, ShuShyan Wong, Brian Gabrielli, Sandra Pavey, Nichole Giles, Alex Pinder, Matthew Wigan, Richard A. Sturm |
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| Rok vydání: | 2012 |
| Předmět: |
DNA Replication
G2 Phase Skin Neoplasms Cell cycle checkpoint Ultraviolet Rays RAD51 DNA Single-Stranded Dermatology Biology Biochemistry S Phase 03 medical and health sciences 0302 clinical medicine Cell Line Tumor CDC2 Protein Kinase medicine Postreplication repair Humans CHEK1 Cyclin B1 Melanoma Molecular Biology Replication protein A 030304 developmental biology Genetics 0303 health sciences integumentary system G1 Phase Cell Cycle Checkpoints Cell Biology G2-M DNA damage checkpoint medicine.disease 3. Good health Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) Epidermal Cells 030220 oncology & carcinogenesis Mutation Ataxia-telangiectasia Epidermis Nucleotide excision repair |
| Zdroj: | Journal of Investigative Dermatology. 132:1681-1688 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2012.41 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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