At the molecular level, PARP identifies DNA damage and signals the need for repair . The steps involved are outlined in the figure below.
Step 1: Any type of DNA damage, such as a single-strand break, is detected by PARP1 via its DNA binding domain.
Step 2: This triggers activation of PARP1 resulting in successive additions of ADP-ribose units to PARP and leads to the formation of long and branched chains of poly (ADP-ribose) (PAR).
Step 3: These PAR chains create a scaffold that recruits critical proteins for DNA repair.
Figure 1: Role of PARP1 in recruiting critical proteins for DNA repair.
Although this is how PARP works, it is now known that the main action of PARP inhibitors is not by directly inhibiting PARP activation, but by trapping PARP onto damaged DNA. You can read more about this process in the next section.
- Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].