DNA repair protein XRCC4 (XRCC4)

DNA repair protein XRCC4 (XRCC4) is a core factor in the non-homologous end joining (NHEJ) pathway, responsible for the repair of DNA double-strand breaks (DSBs)[1][2][3][4][5]. XRCC4 forms a stable complex with DNA ligase IV, essential for the final ligation step in NHEJ; it acts as a scaffold to stabilize and stimulate the catalytic activity of ligase IV, with its deficiency leading to embryonic lethality in mice and immunodeficiency in humans[1][2][3][5]. Structurally, XRCC4 is a dumbbell-shaped tetramer composed of two dimers, featuring a globular N-terminal head domain and a coiled-coil C-terminal stalk, with critical interaction surfaces for both protein partners and DNA[2][3]. Mutations in XRCC4 contribute to human disease, especially cancer risk and immune dysfunction, and its central role in DNA repair makes it a potential—though not yet clinically validated—target for therapeutic sensitization of tumors to genotoxic treatments[4][5]. Efforts to develop drugs focus on disrupting the XRCC4–ligase IV interface, though safety concerns are significant due to its indispensable role in DNA repair and genomic integrity[1][5].

Other names

X-ray repair cross-complementing protein 4DNA repair protein XRCC4Protein XRCC4XRCC4/ChXRCC4SSMEDX-ray repair complementing defective repair in Chinese hamster cells 4

Inhibitors could block XRCC4–DNA ligase IV complex formation, impeding repair of DNA double-strand breaks and sensitizing tumor cells to DNA-damaging treatments; No direct enzymatic inhibition—mechanism is through protein–protein interaction disruption