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Persistently stalled replication forks inhibit nucleotide excision repair in trans by sequestering Replication protein A.


ABSTRACT: Rev3, the catalytic subunit of DNA polymerase ?, is essential for translesion synthesis of cytotoxic DNA photolesions, whereas the Rev1 protein plays a noncatalytic role in translesion synthesis. Here, we reveal that mammalian Rev3(-/-) and Rev1(-/-) cell lines additionally display a nucleotide excision repair (NER) defect, specifically during S phase. This defect is correlated with the normal recruitment but protracted persistence at DNA damage sites of factors involved in an early stage of NER, while repair synthesis is affected. Remarkably, the NER defect becomes apparent only at 2 h post-irradiation indicating that Rev3 affects repair synthesis only indirectly, rather than performing an enzymatic role in NER. We provide evidence that the NER defect is caused by scarceness of Replication protein A (Rpa) available to NER, resulting from its sequestration at stalled replication forks. Also the induction of replicative stress using hydroxyurea precludes the accumulation of Rpa at photolesion sites, both in Rev3(-/-) and in wild-type cells. These data support a model in which the limited Rpa pool coordinates replicative stress and NER, resulting in increased cytotoxicity of ultraviolet light when replicative stress exceeds a threshold.

SUBMITTER: Tsaalbi-Shtylik A 

PROVIDER: S-EPMC3985633 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Persistently stalled replication forks inhibit nucleotide excision repair in trans by sequestering Replication protein A.

Tsaalbi-Shtylik Anastasia A   Moser Jill J   Mullenders Leon H F LH   Jansen Jacob G JG   de Wind Niels N  

Nucleic acids research 20140123 7


Rev3, the catalytic subunit of DNA polymerase ζ, is essential for translesion synthesis of cytotoxic DNA photolesions, whereas the Rev1 protein plays a noncatalytic role in translesion synthesis. Here, we reveal that mammalian Rev3(-/-) and Rev1(-/-) cell lines additionally display a nucleotide excision repair (NER) defect, specifically during S phase. This defect is correlated with the normal recruitment but protracted persistence at DNA damage sites of factors involved in an early stage of NER  ...[more]

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