title: Replication fork breakage and re-start:  New insights into Rad3/XPD-associated deficiencies.
abstract: Failures in Nucleotide Excision Repair (NER) are generally associated with extreme sun sensitivity, high cancer risks and neurodegeneration. This is explained by the inability to repair UV lesions and oxidative damage, and may be ascribed to a deficiency in the TFIIH complex, which has a dual role in NER and transcription initiation. We have recently uncovered the molecular basis for a specific TFIIH component deficiency, Rad3/XPD, whose consequences are drastically different from other NER failures. Yeast rad3-102 cells partially process NER damage beyond the incision step but do not refill the generated ssDNA gap, as a consequence leading to replication fork breakage. Double-strand breaks are therefore generated that need to be repaired by a Rad52 and MRX-dependent homologous recombination mechanism, which promotes replication re-start via two alternative pathways, one Rad51-dependent, the other Pol32-dependent. On the basis of this study we revisit and discuss our actual view of replication fork breakage and re-start and the molecular mechanisms that explain XPD-associated diseases.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Sevilla, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Moriel-Carretero
authors.forename: A
authors.initials: A
authors.lastname: Aguilera
mesh_terms: D000483:Alleles; D053960:DNA Breaks; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D006801:Humans; D009154:Mutation / Q000235:genetics; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; C061897:Rad3 protein, S cerevisiae; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein