The Importance of Poly(ADP-Ribose) Polymerase as a Sensor of Unligated Okazaki Fragments during DNA Replication

0495899 - ÚMG 2019 RIV US eng J - Článek v odborném periodiku
Hanzlíková, Hana - Kalasová, Ilona - Demin, A.A. - Pennicott, L.E. - Cihlářová, Zuzana - Caldecott, Keith
The Importance of Poly(ADP-Ribose) Polymerase as a Sensor of Unligated Okazaki Fragments during DNA Replication.
Molecular Cell. Roč. 71, č. 2 (2018), s. 319-331. ISSN 1097-2765. E-ISSN 1097-4164
Grant CEP: GA MŠMT(CZ) LM2015062; GA MŠMT LO1419
Institucionální podpora: RVO:68378050
Klíčová slova: base-excision-repair * double-strand breaks * hydroxyurea-induced accumulation * immunodeficient patient 46br * poly-adp-ribose * mouse l-cells * ligase-iii * damaged dna * sv40 dna * in-vitro
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 14.548, rok: 2018

Poly(ADP-ribose) is synthesized by PARP enzymes during the repair of stochastic DNA breaks. Surprisingly, however, we show that most if not all endogenous poly(ADP-ribose) is detected in normal S phase cells at sites of DNA replication. This S phase poly(ADP-ribose) does not result from damaged or misincorporated nucleotides or from DNA replication stress. Rather, perturbation of the DNA replication proteins LIG1 or FEN1 increases S phase poly(ADPribose) more than 10-fold, implicating unligated Okazaki fragments as the source of S phase PARP activity. Indeed, S phase PARP activity is ablated by suppressing Okazaki fragment formation with emetine, a DNA replication inhibitor that selectively inhibits lagging strand synthesis. Importantly, PARP activation during DNA replication recruits the single-strand break repair protein XRCC1, and human cells lacking PARP activity and/or XRCC1 are hypersensitive to FEN1 perturbation. Collectively, our data indicate that PARP1 is a sensor of unligated Okazaki fragments during DNA replication and facilitates their repair.
Trvalý link: http://hdl.handle.net/11104/0288783