DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination (PubMed:9875844). Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs). Associates with NHEJ1/XLF to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired. The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors. Plays a key role in the NHEJ ligation step of the broken DNA during DSB repair via direct interaction with DNA ligase IV (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is completed. XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4's joining activity. Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. Promotes displacement of PNKP from processed strand break termini (By similarity). Acts as an activator of the phospholipid scramblase activity of XKR4 (PubMed:33725486). This form, which is generated upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and interacts with XKR4, thereby promoting phosphatidylserine scramblase activity of XKR4 and leading to phosphatidylserine exposure on apoptotic cell surface (PubMed:33725486). Homodimer and homotetramer in solution. Interacts with NHEJ1/XLF; the interaction is direct and is mediated via a head-to-head interaction between N-terminal head regions. Interacts with LIG4; the LIG4-XRCC4 subcomplex has a 1:2 stoichiometry and XRCC4 is required for LIG4 stability. Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Additional component of the NHEJ complex includes PAXX. Following autophosphorylation, PRKDC dissociates from DNA, leading to formation of the short-range NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Interacts with PRKDC; the interaction is direct. Interacts with XRCC6/Ku70; the interaction is direct. Interacts with APTX and APLF. Forms a heterotetramer with IFFO1; the interaction involves LIG4-free XRCC4 and leads to the relocalization of IFFO1 to the sites of DNA damage. Interacts with PNKP; mainly interacts with PNKP when phosphorylated at Thr-231, but is also able to interact at much lower level with PNKP when not unphosphorylated. Interacts with POLL (DNA polymerase lambda). Interacts with XKR4; interacts with the processed form of XKR4, which is cleaved by caspase. Localizes to site of double-strand breaks. Translocates from the nucleus to the cytoplasm following cleavage by caspase-3 (CASP3). Phosphorylated by PRKDC at the C-terminus in response to DNA damage; Ser-254 and Ser-312 constitute the main phosphorylation sites (PubMed:14599745). Phosphorylation by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex to bridge DNA (By similarity). Phosphorylation by PRKDC does not prevent interaction with NHEJ1/XLF but disrupts ability to bridge DNA and promotes detachment from DNA (By similarity). Phosphorylation at Ser-319 and Ser-320 by PRKDC promotes recognition by the SCF(FBXW7) complex and subsequent ubiquitination via 'Lys-63'-linked ubiquitin (By similarity). Phosphorylation at Thr-231 by CK2 promotes interaction with PNKP; regulating PNKP activity and localization to DNA damage sites (By similarity). Phosphorylation by CK2 promotes interaction with APTX (By similarity). Ubiquitinated at Lys-290 by the SCF(FBXW7) complex via 'Lys-63'-linked ubiquitination, thereby promoting double-strand break repair: the SCF(FBXW7) complex specifically recognizes XRCC4 when phosphorylated at Ser-319 and Ser-320 by PRKDC, and 'Lys-63'-linked ubiquitination facilitates DNA non-homologous end joining (NHEJ) by enhancing association with XRCC5/Ku80 and XRCC6/Ku70. Monoubiquitinated. Undergoes proteolytic processing by caspase-3 (CASP3). This generates the protein XRCC4, C-terminus (XRCC4/C), which translocates to the cytoplasm and activates phospholipid scramblase activity of XKR4, thereby promoting phosphatidylserine exposure on apoptotic cell surface. Mice show growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination (PubMed:9875844). XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells (PubMed:9875844). Belongs to the XRCC4-XLF family. XRCC4 subfamily.