TP53BP1 (tumor protein p53 binding protein 1) is a key regulator of double-strand break (DSB) repair and DNA damage response. It functions as a histone reader, recognizing monoubiquitinated histone H2A at lysine 15 and dimethylated histone H4 at lysine 20 to localize to DSB sites. Upon phosphorylation by ATM kinase, TP53BP1 promotes non-homologous end joining (NHEJ)-mediated repair while antagonizing homologous recombination by counteracting BRCA1 function 1. Beyond DSB repair, TP53BP1 is essential for immunoglobulin class-switch recombination during antibody genesis and participates in telomere maintenance through interaction with PAXIP1. TP53BP1 also acts as a tumor suppressor through p53-dependent mechanisms. Extended mitosis generates TP53BP1-USP28-p53 complexes that are transmitted to daughter cells and elicit p53 responses preventing proliferation of cells with genomic instability 2. This mitotic checkpoint is lost in p53-mutant cancers, classifying TP53BP1 as a tumor suppressor. Clinically, TP53BP1 variants show protective effects against squamous cell carcinoma of the head and neck when co-inherited with specific TP53 polymorphisms 3. In homologous recombination-deficient breast cancers, loss-of-function mutations in TP53BP1 emerge as a mechanism of acquired resistance to PARP inhibitors 4, establishing it as a therapeutic target in HRD-driven malignancies.