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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00565988" target="_blank" >RIV/61388971:_____/22:00565988 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/22:00565988

Výsledek na webu

<a href="https://www.nature.com/articles/s41594-022-00747-1" target="_blank" >https://www.nature.com/articles/s41594-022-00747-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41594-022-00747-1" target="_blank" >10.1038/s41594-022-00747-1</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

Biochemical and cell-based assays reveal 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 anti-cancer compounds. 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

Biochemical and cell-based assays reveal 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 anti-cancer compounds. 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Structural & Molecular Biology

ISSN

1545-9993

e-ISSN

1545-9985

Svazek periodika

29

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

23

Strana od-do

329-351

Kód UT WoS článku

000772742100002

EID výsledku v databázi Scopus

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