title: Replication protein A safeguards genome integrity by controlling NER incision events.
abstract: Single-stranded DNA gaps that might arise by futile repair processes can lead to mutagenic events and challenge genome integrity. Nucleotide excision repair (NER) is an evolutionarily conserved repair mechanism, essential for removal of helix-distorting DNA lesions. In the currently prevailing model, NER operates through coordinated assembly of repair factors into pre- and post-incision complexes; however, its regulation in vivo is poorly understood. Notably, the transition from dual incision to repair synthesis should be rigidly synchronized as it might lead to accumulation of unprocessed repair intermediates. We monitored NER regulatory events in vivo using sequential UV irradiations. Under conditions that allow incision yet prevent completion of repair synthesis or ligation, preincision factors can reassociate with new damage sites. In contrast, replication protein A remains at the incomplete NER sites and regulates a feedback loop from completion of DNA repair synthesis to subsequent damage recognition, independently of ATR signaling. Our data reveal an important function for replication protein A in averting further generation of DNA strand breaks that could lead to mutagenic and recombinogenic events.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, 2333 RC Leiden, Netherlands.
authors.forename: René M
authors.initials: RM
authors.lastname: Overmeer
authors.forename: Jill
authors.initials: J
authors.lastname: Moser
authors.forename: Marcel
authors.initials: M
authors.lastname: Volker
authors.forename: Hanneke
authors.initials: H
authors.lastname: Kool
authors.forename: Alan E
authors.initials: AE
authors.lastname: Tomkinson
authors.forename: Albert A
authors.initials: AA
authors.lastname: van Zeeland
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Maria
authors.initials: M
authors.lastname: Fousteri
mesh_terms: D002478:Cells, Cultured; D004260:DNA Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015894:Genome, Human; D006801:Humans; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D004277:DNA, Single-Stranded; D051716:Replication Protein A