Figure 5.

The DNA damage response, highlighting cross-talk between the cell cycle and DNA repair. (a) Base excision repair (BER) is the first line of defence when DNA damage occurs. PARP activation by SSB recruits XRCC1, Pol β, and Lig III to repair the DNA. (b) When PARP is inhibited, SSB accumulate, causing stalled replication forks, and single-ended DSBs, causing fork collapse. BRCA2 facilitates replacing RPA with repair protein RAD51, which subsequently forms a filament to search for the specific homologous sequence on the sister chromatid as a template for repair and re-start. PARPi-induced replication stress activates ATR, which initiates a signalling cascade. ATR activates CHK1 by phosphorylation at serine 345, causing CHK1 to autophosphorylate at serine 296, to achieve full activation. CHK1 inactivates CDC25A/C, thereby preventing the removal of inhibitory phosphorylation on CDK2 and 1, respectively, thus preventing S-phase progression and mitosis. The pathway also promotes HRR as CHK1 activates BRCA2 and RAD51 by phosphorylation, and ATR also phosphorylates RAD51.