PARP inhibition impedes the maturation of nascent DNA strands during DNA replication

Vaitsiankova, Alina, Burdova, Kamila, Sobol, Margarita, Gautam, Amit, Benada, Oldrich, Hanzlikova, Hana and Caldecott, Keith W (2022) PARP inhibition impedes the maturation of nascent DNA strands during DNA replication. Nature Structural and Molecular Biology, 29. pp. 329-338. ISSN 1545-9993

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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.

Item Type: Article
Keywords: DNA, DNA Damage, DNA Repair, DNA Replication, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 01 Nov 2022 11:32
Last Modified: 01 Nov 2022 11:45

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Project NameSussex Project NumberFunderFunder Ref
UnsetUnsetCancer Research UKC6563/A27322