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PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
A. Vaitsiankova, K. Burdova, M. Sobol, A. Gautam, O. Benada, H. Hanzlikova, KW. Caldecott
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
C6563/A27322
Cancer Research UK - United Kingdom
NLK
ProQuest Central
from 2004-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2004-01-01 to 1 year ago
- MeSH
- DNA genetics MeSH
- DNA Repair MeSH
- Poly(ADP-ribose) Polymerase Inhibitors * pharmacology MeSH
- Poly (ADP-Ribose) Polymerase-1 genetics MeSH
- DNA Damage MeSH
- DNA Replication * MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Poly(ADP-ribose) polymerase 1 (PARP1) is implicated in the detection and processing of unligated Okazaki fragments and other DNA replication intermediates, highlighting such structures as potential sources of genome breakage induced by PARP inhibition. Here, we show that PARP1 activity is greatly elevated in chicken and human S phase cells in which FEN1 nuclease is genetically deleted and is highest behind DNA replication forks. PARP inhibitor reduces the integrity of nascent DNA strands in both wild-type chicken and human cells during DNA replication, and does so in FEN1-/- cells to an even greater extent that can be detected as postreplicative single-strand nicks or gaps. Collectively, these data show that PARP inhibitors impede the maturation of nascent DNA strands during DNA replication, and implicate unligated Okazaki fragments and other nascent strand discontinuities in the cytotoxicity of these compounds.
References provided by Crossref.org
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