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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
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
C6563/A27322
Cancer Research UK - United Kingdom
NLK
ProQuest Central
od 2004-01-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 2004-01-01 do Před 1 rokem
- MeSH
- DNA genetika MeSH
- oprava DNA MeSH
- PARP inhibitory * farmakologie MeSH
- poly(ADP-ribosa)polymerasa 1 genetika MeSH
- poškození DNA MeSH
- replikace DNA * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
Citace poskytuje Crossref.org
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