Figure 1.

Overview of DNA double-strand break repair mechanisms and PARP inhibitor function. PARP inhibitors (PARPi) act mainly in two ways, both by inhibiting the catalytic activity of PARP1 (the so-called PARylation) and trapping PARP1 at sites of single-stranded DNA breaks (SSBs). In both cases, unrepaired SSBs lead to double-stranded DNA breaks (DSBs). Homologous recombination repair (HRR) is an error-free mechanism that resolved DSBs. HRR deficiency (HRD) induces activation of the more error-prone non-homologous end-joining or microhomology-mediated end-joining pathways; cells repaired via these mechanisms undergo complex genomic rearrangements and apoptosis. HRR is activated by the binding of the MRN complex (Mre11, Rad50, and Nbs1) to DSB ends; the MRN complex initiates DNA end resection, leading to the formation of single-strand DNA (ssDNA) at the extremity of the DSB; ssDNA is protected from degradation by the loading of replication protein A (RPA). The MRN complex recruits and activates ATM. Once activated, ATM phosphorylates several proteins involved in the HRR pathway, such as CHEK2. FANCD2 contributes to BRCA1 activation once monoubiquitinated by FANC and phosphorylated by ATM. The complex BRCA1-BARD1 facilitates DNA end resection and interacts with PALB2 phosphorylated by CHEK2. PALB2 promotes the recruitment of BRCA2. PALB2 and BRCA2 remove RPA and facilitate the assembly of the RAD51 recombinase nucleoprotein filament. RAD51 nucleoprotein filament, Shu complex and RAD51 paralogs mediate the D-loop formation and strand invasion of ssDNA into the intact sister chromatid, searching a homologous template for DNA synthesis by DNA polymerase (DNA pol). The repaired DNA is resolved by synthesis-dependent strand annealing.