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

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 el...

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Autores principales: Vaitsiankova, Alina, Burdova, Kamila, Sobol, Margarita, Gautam, Amit, Benada, Oldrich, Hanzlikova, Hana, Caldecott, Keith W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010290/
https://www.ncbi.nlm.nih.gov/pubmed/35332322
http://dx.doi.org/10.1038/s41594-022-00747-1
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author Vaitsiankova, Alina
Burdova, Kamila
Sobol, Margarita
Gautam, Amit
Benada, Oldrich
Hanzlikova, Hana
Caldecott, Keith W.
author_facet Vaitsiankova, Alina
Burdova, Kamila
Sobol, Margarita
Gautam, Amit
Benada, Oldrich
Hanzlikova, Hana
Caldecott, Keith W.
author_sort Vaitsiankova, Alina
collection PubMed
description 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.
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spelling pubmed-90102902022-04-29 PARP inhibition impedes the maturation of nascent DNA strands during DNA replication Vaitsiankova, Alina Burdova, Kamila Sobol, Margarita Gautam, Amit Benada, Oldrich Hanzlikova, Hana Caldecott, Keith W. Nat Struct Mol Biol Article 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. Nature Publishing Group US 2022-03-24 2022 /pmc/articles/PMC9010290/ /pubmed/35332322 http://dx.doi.org/10.1038/s41594-022-00747-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Vaitsiankova, Alina
Burdova, Kamila
Sobol, Margarita
Gautam, Amit
Benada, Oldrich
Hanzlikova, Hana
Caldecott, Keith W.
PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
title PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
title_full PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
title_fullStr PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
title_full_unstemmed PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
title_short PARP inhibition impedes the maturation of nascent DNA strands during DNA replication
title_sort parp inhibition impedes the maturation of nascent dna strands during dna replication
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010290/
https://www.ncbi.nlm.nih.gov/pubmed/35332322
http://dx.doi.org/10.1038/s41594-022-00747-1
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