PARP3 is a mono-ADP-ribosyltransferase that catalyzes post-translational modification of target proteins and DNA, playing a central role in DNA damage response and genome stability 1. Unlike PARP1 and PARP2, PARP3 mediates only mono-ADP-ribosylation, not poly-ADP-ribosylation 2. PARP3 functions primarily in single-strand break repair by mono-ADP-ribosylating histone H2B at nicked nucleosomes 3, and directly ADP-ribosylates DNA strand break termini 2. The enzyme cooperates with XRCC5-XRCC6 (Ku complex) to promote accurate non-homologous end-joining (NHEJ) and limit end-resection 4. PARP3 also suppresses G-quadruplex structures in response to DNA damage 5. Clinically, dysregulated PARP3 activity drives genomic instability and contributes to oncogenesis. PARP3 promotes chr3 rearrangements including translocations and class-switch recombination 4, and is identified as a key driver of tumor aggressiveness in breast cancer 1. Beyond DNA repair, PARP3 regulates gene expression through interactions with histone methyltransferases and participates in metabolic processes 6. PARP3 shows synthetic lethality with BRCA1 deficiency, making it a promising therapeutic target for BRCA1-associated cancers 7. PARP inhibitors targeting PARP3 show therapeutic potential in oncology and emerging applications in cardiovascular disease and metabolic disorders 5.