Journal
MOLECULAR CELL
Volume 71, Issue 2, Pages 319-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.06.004
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Funding
- MRC [MR/P010121/1]
- CRUK [C6563/A16771]
- ERC (SIDSCA) [694996]
- Wellcome Trust [110578/Z/15/Z]
- Wellcome Trust ISSF award
- MEYS [LM2015062]
- OPPK [CZ.2.16/3.1.00/21547]
- NPU I [LO1419]
- MRC [MR/P010121/1] Funding Source: UKRI
- Wellcome Trust [110578/Z/15/Z] Funding Source: Wellcome Trust
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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.
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