Tumor protein p53-binding protein 1 (53BP1) (53BP1)

Tumor protein p53-binding protein 1 (53BP1) is a large scaffold protein and a central mediator of the DNA damage response (DDR) [2, 4]. It is recruited to the sites of DNA double-strand breaks (DSBs) through the recognition of specific histone modifications, namely dimethylated histone H4 lysine 20 (H4K20me2) and ubiquitinated histone H2A lysine 15 (H2AK15ub) [4, 39]. Once localized, 53BP1 promotes the non-homologous end joining (NHEJ) repair pathway and actively suppresses homologous recombination (HR) by limiting DNA end resection [2, 6, 24]. In oncology, 53BP1 is a critical determinant of sensitivity to PARP inhibitors; its loss in BRCA1-deficient cells can restore HR and lead to drug resistance [2, 35]. Therapeutic strategies are currently exploring 53BP1 antagonists, such as small molecules targeting its Tudor domain or engineered ubiquitin variants like i53, to sensitize tumors to DNA-damaging therapies or to enhance the efficiency of homology-directed repair in CRISPR-Cas9 genome editing [22, 27, 29].

Other names

TP53BP1p53BP1TDRD30p202Tumor suppressor p53-binding protein 1

53BP1 promotes non-homologous end joining (NHEJ) by binding to damaged chromatin and protecting DNA ends from resection [2, 4]. Antagonists (e.g., UNC9512, i53) bind to the 53BP1 tandem Tudor domain, blocking its recruitment to DNA damage sites, which shifts repair toward homologous recombination or increases sensitivity to DNA-damaging agents [22, 28, 29].