Poly ADP-ribose polymerase (PARP) proteins directly contribute to a wide range of essential cellular processes, including DNA replication, transcription, chromatin remodeling, metabolism, programmed cell death, and the response to DNA damage [1], [2], [3], [4], [5]. Among the 17 PARP family members (PARP1–17), only PARP1, PARP2, and PARP3 are known to be activated by DNA breaks [2], [6]. Of these, PARP1 is the most highly expressed, is responsible for the vast majority of cellular PARylation events, and is by far the most extensively studied [2], [7].

PARP1 is a highly abundant nuclear protein that is conserved in single and multicellular eukaryotes, though it is notably absent from the model yeasts, S. cerevisiae and S. pombe [8]. Upon activation, PARP1 uses nicotinamide adenine dinucleotide (NAD+) to catalyze the addition of poly (ADP)-ribose (PAR) chains and branches, a negatively charged post-translational modification, onto a myriad of targets [3], [5], [9], [10]. PARP1 recognizes and binds to DNA lesions within seconds following damage [11], where its binding to DNA breaks leads to activation, autoPARylation, and PARylation of chromatin, DNA damage and repair (DDR) proteins, or even nucleic acids [3], [5], [9], [10].

Although the role of PARP in promoting single-strand break repair is well established, its functions at double-strand breaks (DSBs) are more intricate, in part because multiple repair pathways operate in parallel and in competition at these highly toxic lesions. Because unrepaired DSBs can lead to genome instability, cell death, or cancer [12], it is critical to understand how PARP contributes to their repair. This question is especially relevant given that PARP inhibitors are used as first-line maintenance therapies for homologous recombination (HR)-deficient cancers due to their synthetic lethality with HR loss [13], [14], [15]. Defining the precise role of PARP in DSB repair is therefore essential to fully understand the cellular consequences of PARP inhibitor treatment. This review summarizes current knowledge on the involvement of PARP proteins in DSB repair, with a primary focus on PARP1, while also addressing the functions of PARP2 and PARP3.