期刊
DNA REPAIR
卷 14, 期 -, 页码 27-38出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2013.12.005
关键词
UV damage bypass; NER; TLS DNA polymerase eta; Cell cycle progression; Replication fork; DNA strand breaks; gamma H2AX
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Sao Paulo, Brazil)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brasilia, DF, Brazil)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brasilia, DF, Brazil)
- Centre National de Recherche Scientifique (CNRS, France)
- Association Francaise des Myopathies (Evry, France)
- Association Francaise des Enfants de la Lune (Tercis, France)
- ANPCyT (Argentina)
- FAPESP
- French government (Ministere de l'Enseignement Superieur et de la Recherche)
Ultraviolet (UV)-induced DNA damage are removed by nucleotide excision repair (NER) or can be tolerated by specialized translesion synthesis (TLS) polymerases, such as Pol eta. TLS may act at stalled replication forks or through an S-phase independent gap-filling mechanism. After UVC irradiation, Pol eta-deficient (XP-V) human cells were arrested in early S-phase and exhibited both single-strand DNA (ssDNA) and prolonged replication fork stalling, as detected by DNA fiber assay. In contrast, NER deficiency in XP-C cells caused no apparent defect in S-phase progression despite the accumulation of ssDNA and a G2-phase arrest. These data indicate that while Pol eta is essential for DNA synthesis at ongoing damaged replication forks, NER deficiency might unmask the involvement of tolerance pathway through a gap-filling mechanism. ATR knock down by siRNA or caffeine addition provoked increased cell death in both XP-V and XP-C cells exposed to low-dose of UVC, underscoring the involvement of ATR/Chk1 pathway in both DNA damage tolerance mechanisms. We generated a unique human cell line deficient in XPC and Pol eta proteins, which exhibited both S- and G2-phase arrest after UVC irradiation, consistent with both single deficiencies. In these XP-C/Pol eta(KD) cells, UVC-induced replicative intermediates may collapse into double-strand breaks, leading to cell death. In conclusion, both TLS at stalled replication forks and gap-filling are active mechanisms for the tolerance of UVC-induced DNA damage in human cells and the preference for one or another pathway depends on the cellular genotype. (C) 2013 Elsevier B.V. All rights reserved.
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