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DDB2-Independent Role for p53 in the Recovery from Ultraviolet Light-Induced Replication Arrest

Lawton J. Stubbert, Jeff D. Hamill, Jennifer C. Spronck, Jennifer M. Smith, Cecilia Becerril and Bruce McKay

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Ultraviolet light (UV light) induces helix distorting DNA lesions that pose a block to replicative DNA polymerases. Recovery from this replication arrest is reportedly impaired in nucleotide excision repair (NER)-deficient xeroderma pigmentosum (XP) fibroblasts and primary fibroblasts lacking functional p53. These independent observations suggested that the involvement of p53 in the recovery from UV-induced replication arrest was related to its role in regulating the global genomic subpathway of NER (GG-NER). Using primary human fibroblasts, we confirm that the recovery from UV-induced replication arrest is impaired in cells lacking functional p53 and in primary XP fibroblasts derived from complementation groups A or C (XP-A and XP-C) that are defective in GG-NER. Surprisingly, DNA synthesis recovered normally in GG-NER-deficient XP complementation group E (XP-E) cells that carry mutations in the p53 regulated DNA repair gene DDB2 and are specifically defective in the repair of cyclobutane pyrimidine dimers (CPD) but not pyrimidine (6-4) pyrimidone photoproducts. Disruption of p53 in these XP-E fibroblasts prevented the recovery from UV-induced replication arrest. Therefore, the roles of p53 and GG-NER in the recovery from UV-induced replication are separable and DDB2-independent. These results further indicate that primary human fibroblasts expressing functional p53 efficiently replicate DNA containing CPD whereas p53-deficient cells do not, consistent with a role for p53 in permitting translesion DNA synthesis of these DNA lesions.

Authors

Lawton J. Stubbert

University of Ottawa; Ottawa, Ontario, Canada

Jeff D. Hamill

Ottawa Health Research Institute; Ottawa, Ontario, Canada

Jennifer C. Spronck

Ottawa Health Research Institute; Ottawa, Ontario, Canada

Jennifer M. Smith

Ottawa Health Research Institute; Ottawa, Ontario, Canada

Cecilia Becerril

Ottawa Health Research Institute; Ottawa, Ontario, Canada

Bruce McKay

Ottawa Health Research Institute

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.