Figure 3. Roles of PARP1 in DNA damage repair.

PARP1 binds to sites of DNA damage, is rapidly activated, and catalyzes autoADPRylation, as well as transmodification of local substrate proteins, playing important roles in various DNA repair pathways.

(A) Activated PARP1 at sites of single-strand breaks (SSBs) recruits DNA repair effectors, such as X-ray repair cross-complementing protein 1 (XRCC1), to mediate DNA repair. AutoADPRylation causes the dissociation of PARP1 from the DNA damage site, which is ultimately required for the efficient DNA repair.

(B) In response to double-strand breaks (DSBs), activated PARP1 recruits the MRE11-RAD50NBS1 (MRN) complex and other repair factors to the sites of damage for homologous recombination (HR)-mediated repair. PARP1 also differentially regulates classical and alternative non-homologous end-joining (NHEJ) repair pathways. PARP1 binds to DSBs in direct competition with Ku70/80 proteins, thus inhibiting the classical pathway of NHEJ that utilizes Ku, DNA-PKcs, DNA ligase IV, and XRCC4. Conversely, PARP1 mediates the recruitment of MRN and CtIP to DSBs to promotes alternative NHEJ (Alt-EJ).

(C) PARP1 links DNA damage to DNA replication by regulating DNA replication fork progression during replication stress. PARP1 is activated at the stalled replication forks in response to replication stress. Activated PARP1 may promote replication fork reversal or stabilization by multiple distinct mechanisms, such as (1) inhibiting the ATP-dependent DNA helicase Q1 (RECQ1), which is responsible for restart of the stalled replication fork or (2) inhibiting fork degradation by MRN and EXO1 through the recruitment of BRCA1. Conflicting studies have suggested an active role of PARP1 in replication fork restart through MRE11 based on the prevention or delay of replication restart upon PARP1 depletion, but the evidence directly linking PARP1 and MRE11 during fork restart is limited.