Activation of the Fanconi anemia/BRCA pathway and recombination repair in the cellular response to solar ultraviolet light.
Recombination repair plays an important role in the processing of DNA double-strand breaks (DSB) and DNA cross-links, and has been suggested to be mediated by the activation of the Fanconi anemia (FA)/BRCA pathway. Unlike DNA damage generated by ionizing radiation or DNA cross-linking, UV light-induced DNA damage is not commonly thought to require recombination for processing, as UV light does not directly induce DSBs or DNA cross-links. To elucidate the role of recombination repair in the cellular response to UV, we studied the FA/BRCA pathway in primary skin cells exposed to solar-simulated light. UV-induced monoubiquitination of the FANCD2 protein and formation of FANCD2 nuclear foci confirmed the activation of the pathway by UV light. This was only observed when cells were irradiated during S phase and was not caused by directly UV-induced DSBs. UV-exposed cells did not exhibit FANCD2 nuclear foci once they entered mitosis or when growth-arrested. In addition, UV-induced nuclear foci of the recombination proteins, RAD51 and BRCA1, colocalized with FANCD2 foci. We suggest that in response to UV light, when nucleotide excision repair failed to repair, or when translesional DNA synthesis failed to bypass UV-induced DNA photoproducts, the FA/BRCA pathway mediates the recombination repair of replication forks stalled at DNA photoproducts as a third line of defense.
Dunn
Jessica
J
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Potter
Marisa
M
Rees
Adam
A
Rünger
Thomas M
TM
D019313:BRCA1 Protein / Q000378:metabolism*; D002453:Cell Cycle / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008297:Male; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects*; D013997:Time Factors; D014466:Ultraviolet Rays
D019313:BRCA1 Protein; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051135:Rad51 Recombinase