The importance of Poly(ADP-Ribose) Polymerase as a sensor of unligated Okazaki fragments during DNA replication

Hanzlikova, Hana, Kalasova, Ilona, Demin, Annie, Pennicott, Lewis and Caldecott, Keith (2018) The importance of Poly(ADP-Ribose) Polymerase as a sensor of unligated Okazaki fragments during DNA replication. Molecular Cell, 71 (2). pp. 319-331. ISSN 1097-2765

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Abstract

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

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Depositing User: Paula Amiet-West
Date Deposited: 13 Jul 2018 11:36
Last Modified: 02 Jul 2019 15:04
URI: http://sro.sussex.ac.uk/id/eprint/77126

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