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.

Department of Genome Dynamics Institute of Molecular Genetics of the ASCR v v i 142 20 Prague 4 Czech Republic

Genome Damage and Stability Centre and Sussex Drug Discovery Centre School of Life Sciences University of Sussex Falmer Brighton BN1 9RQ UK

Genome Damage and Stability Centre and Sussex Drug Discovery Centre School of Life Sciences University of Sussex Falmer Brighton BN1 9RQ UK; Department of Genome Dynamics Institute of Molecular Genetics of the ASCR v v i 142 20 Prague 4 Czech Republic

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Mol Cell. 2018 Sep 20;71(6):877-878. doi: 10.1016/j.molcel.2018.08.045. PubMed

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Dispensability of HPF1 for cellular removal of DNA single-strand breaks

BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks

PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair

Emetine blocks DNA replication via proteosynthesis inhibition not by targeting Okazaki fragments

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

Histone Variant macroH2A1.1 Enhances Nonhomologous End Joining-dependent DNA Double-strand-break Repair and Reprogramming Efficiency of Human iPSCs

XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair

Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair

ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition