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Titolo:
Replication-mediated DNA damage by camptothecin induces phosphorylation ofRPA by DNA-dependent protein kinase and dissociates RPA : DNA-PK complexes
Autore:
Shao, RG; Cao, CX; Zhang, HL; Kohn, KW; Wold, MS; Pommier, Y;
Indirizzi:
NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA Univ Iowa Iowa City IA USA 52242 a, Dept Biochem, Iowa City, IA 52242 USA
Titolo Testata:
EMBO JOURNAL
fascicolo: 5, volume: 18, anno: 1999,
pagine: 1397 - 1406
SICI:
0261-4189(19990301)18:5<1397:RDDBCI>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
SINGLE-STRANDED-DNA; S-PHASE CHECKPOINT; RADIATION-INDUCED PHOSPHORYLATION; SIMIAN VIRUS-40 DNA; ATAXIA-TELANGIECTASIA; BINDING PROTEIN; TOPOISOMERASE-I; CELL-LINES; SACCHAROMYCES-CEREVISIAE; CLEAVABLE COMPLEXES;
Keywords:
camptothecin; DNA damage; DNA-dependent protein kinase; RPA2 phosphorylation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Pommier, Y NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 sic Sci, NIH, Bethesda, MD 20892 USA
Citazione:
R.G. Shao et al., "Replication-mediated DNA damage by camptothecin induces phosphorylation ofRPA by DNA-dependent protein kinase and dissociates RPA : DNA-PK complexes", EMBO J, 18(5), 1999, pp. 1397-1406

Abstract

Replication protein A (RPA) is a DNA single-strand binding protein essential for DNA replication, recombination and repair. In human cells treated with the topoisomerase inhibitors camptothecin or etoposide (VP-16), we find that RPA2, the middle-sized subunit of RPA, becomes rapidly phosphorylated,This response appears to be due to DNA-dependent protein kinase (DNA-PK) and to be independent of p53 or the ataxia telangiectasia mutated (ATM) protein. RPA2 phosphorylation in response to camptothecin required ongoing DNA replication. Camptothecin itself partially inhibited DNA synthesis, and this inhibition followed the same kinetics as DNA-PK activation and RPA2 phosphorylation, DNA-PK activation and RPA2 phosphorylation were prevented by the cell-cycle checkpoint abrogator 7-hydroxystaurosporine (UCN-01), which markedly potentiates camptothecin cytotoxicity. The DNA-PK catalytic subunit (DNA-PKcs) was found to bind RPA which was replaced by the Ku autoantigen upon camptothecin treatment. DNA-PKcs interacted directly with RPA1 in vitro. We propose that the encounter of a replication fork with a topoisomerase-DNA cleavage complex could lead to a juxtaposition of replication fork-associated RPA and DNA double-strand end-associated DNA-PK, leading to RPA2 phosphorylation which may signal the presence of DNA damage to an S-phase checkpoint mechanism.

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Documento generato il 29/09/20 alle ore 23:59:45