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

0565988 - ÚMG 2023 RIV US eng J - Článek v odborném periodiku
Vaitsiankova, A. - Burdova, K. - Sobol, Margaryta - Gautam, A. - Benada, Oldřich - Hanzlíková, Hana - Caldecott, Keith
PARP inhibition impedes the maturation of nascent DNA strands during DNA replication.
Nature Structural & Molecular Biology. Roč. 29, č. 4 (2022), s. 329-351. ISSN 1545-9993. E-ISSN 1545-9985
Grant CEP: GA MŠMT(CZ) LM2018129; GA MŠMT(CZ) EF18_046/0016045; GA MŠMT(CZ) EF16_013/0001775
Výzkumná infrastruktura: Czech-BioImaging II - 90129
Institucionální podpora: RVO:68378050 ; RVO:61388971
Klíčová slova: Homologous recombination * Synthetic lethality * Okazaki fragments * Fork progression * Cells * Repair * Damage * Endonuclease * Mechanism * Restart
Obor OECD: Biochemistry and molecular biology; Biochemistry and molecular biology (MBU-M)
Impakt faktor: 16.8, rok: 2022
Způsob publikování: Open access
https://www.nature.com/articles/s41594-022-00747-1

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.
Trvalý link: https://hdl.handle.net/11104/0337428