Abstract
PARP-1 is rapidly recruited and activated by DNA double-strand breaks (DSBs). Upon activation, PARP-1 synthesizes a structurally complex polymer composed of ADP-ribose units that facilitates local chromatin relaxation and the recruitment of DNA repair factors. Here, we identify a function for PARP-1 in DNA DSB resection. Remarkably, inhibition of PARP-1 leads to hyperresected DNA DSBs. We show that loss of PARP-1 and hyperresection are associated with loss of Ku, 53BP1 and RIF1 resection inhibitors from the break site. DNA curtains analysis show that EXO1-mediated resection is blocked by PARP-1. Furthermore, PARP-1 abrogation leads to increased DNA resection tracks and an increase of homologous recombination in cellulo. Our results, therefore, place PARP-1 activation as a critical early event for DNA DSB repair activation and regulation of resection. Hence, our work has direct implications for the clinical use and effectiveness of PARP inhibition, which is prescribed for the treatment of various malignancies.
Highlights
Poly(ADP-ribose) polymerase-1 (PARP-1) is rapidly recruited and activated by DNA double-strand breaks (DSBs)
We demonstrated that MRE11 and NBS1, which are core components of the early DSB sensing complex MRN, are recruited in a PARP-1-dependent manner to laserinduced DNA damage tracks
The initial rapid accumulation of PARP-1 at sites of damage was followed by a steady reduction over the 10 min, while in the presence of BMN 673, PARP-1 is lost from the damage site more slowly, possibly due to trapping at DSBs38
Summary
PARP-1 is rapidly recruited and activated by DNA double-strand breaks (DSBs). PARP-1 synthesizes a structurally complex polymer composed of ADP-ribose units that facilitates local chromatin relaxation and the recruitment of DNA repair factors. Inhibition of PARP-1 leads to hyperresected DNA DSBs. We show that loss of PARP-1 and hyperresection are associated with loss of Ku, 53BP1 and RIF1 resection inhibitors from the break site. The eukaryotic genome is confronted with up to 50 endogenous DNA double-strand breaks (DSBs)[1]. These are extremely hazardous for a cell, because if left unrepaired, DSBs can have pathological consequences, such as cell death, or drive cells to genomic instability and tumor development.
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