title: How do drug-induced topoisomerase I-DNA lesions signal to the molecular interaction network that regulates cell cycle checkpoints, DNA replication, and DNA repair?
abstract: Recent results suggest that potentially lethal DNA lesions may result when replication forks encounter trapped topoisomerase-DNA complexes or some other types of DNA damage. Such events produce what are called replication-encounter lesions. These lesions have the characteristic that they may allow single stranded DNA-associated replication protein A (RPA) to become juxtaposed to dsDNA end-associated DNA-protein kinase. Our results suggest that DNA-protein kinases may then hyperphosphorylate the RPA2 subunit. We discuss a possible pathway by which hyperphosphorylation of RPA2 could lead to the release of active p53. This could constitute a pathway for signaling the presence of replication-encounter lesions to the p53-dependent cell cycle arrest and/or apoptosis initiator systems.
authors.affiliation: Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Kohn
authors.forename: R G
authors.initials: RG
authors.lastname: Shao
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D018741:Replication Origin; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin