TP53BP1 is a critical DNA damage response protein that promotes non-homologous end joining (NHEJ) repair of double-strand breaks (DSBs) while antagonizing homologous recombination (HR) repair 1. The protein functions by recognizing histone modifications at DSB sites, specifically binding to monoubiquitinated histone H2A at lysine-15 and dimethylated histone H4 at lysine-20 1. Upon DNA damage, ATM-mediated phosphorylation promotes TP53BP1 interaction with RIF1 and recruitment to DSB sites. TP53BP1 plays essential roles in immunoglobulin class-switch recombination during antibody genesis and telomere maintenance 2. The protein also functions in cell cycle control, forming complexes with USP28 and p53 during extended mitosis that are transmitted to daughter cells, triggering p53-mediated growth arrest in progeny of cells experiencing prolonged mitosis 3. Clinically, TP53BP1 serves as a tumor suppressor, and loss-of-function mutations contribute to PARP inhibitor resistance in BRCA1/2-deficient breast cancers by restoring HR capacity 2. The protein shows age-related expression changes and may serve as a biomarker for vascular aging 4. Functional variants in TP53BP1's Tudor domain affect USP28 binding, highlighting its regulatory complexity in DNA damage responses 5.