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FUNCTION DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination (PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:16412978, PubMed:17124166, PubMed:17290226, PubMed:22228831, PubMed:25597996, PubMed:25742519, PubMed:25934149, PubMed:26100018, PubMed:26774286, PubMed:8548796). Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs) (PubMed:15385968, PubMed:20852255, PubMed:26774286, PubMed:27437582). 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 (PubMed:21768349, PubMed:21775435, PubMed:22287571, PubMed:26100018, PubMed:27437582, PubMed:28500754). 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 (PubMed:27437582). The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors (PubMed:27437582). 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 (PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:19837014, PubMed:9242410). XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4's joining activity (PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:21982441, PubMed:22228831, PubMed:9242410). 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 (PubMed:10757784, PubMed:10854421). Promotes displacement of PNKP from processed strand break termini (PubMed:20852255, PubMed:28453785).FUNCTION 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).SUBUNIT Homodimer and homotetramer in solution (PubMed:11080143, PubMed:25574025, PubMed:25670504, PubMed:25941166, PubMed:31548606, PubMed:17567543). Interacts with NHEJ1/XLF; the interaction is direct and is mediated via a head-to-head interaction between N-terminal head regions (PubMed:16439205, PubMed:17567543, PubMed:18158905, PubMed:20558749, PubMed:21768349, PubMed:21775435, PubMed:21936820, PubMed:22228831, PubMed:22287571, PubMed:22658747, PubMed:26100018, PubMed:27437582). Interacts with LIG4; the LIG4-XRCC4 subcomplex has a 1:2 stoichiometry and XRCC4 is required for LIG4 stability (PubMed:11702069, PubMed:12517771, PubMed:17290226, PubMed:19332554, PubMed:21982441, PubMed:22658747, PubMed:24984242, PubMed:25934149, PubMed:9242410, PubMed:9259561, PubMed:17567543). 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 (PubMed:10757784, PubMed:10854421, PubMed:12547193, PubMed:17124166, PubMed:22658747, PubMed:26774286, PubMed:33854234, PubMed:34352203). Additional component of the NHEJ complex includes PAXX (PubMed:16439205). 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 (PubMed:33854234). Interacts with PRKDC; the interaction is direct (PubMed:12509254). Interacts with XRCC6/Ku70; the interaction is direct (PubMed:17124166). Interacts with APTX and APLF (PubMed:15380105, PubMed:17353262, PubMed:17396150, PubMed:18077224). Forms a heterotetramer with IFFO1; the interaction involves LIG4-free XRCC4 and leads to the relocalization of IFFO1 to the sites of DNA damage (PubMed:31548606). Interacts with PNKP; mainly interacts with PNKP when phosphorylated at Thr-233, but is also able to interact at much lower level with PNKP when not unphosphorylated (PubMed:15385968, PubMed:20852255, PubMed:28453785). Interacts with POLL (DNA polymerase lambda) (PubMed:30250067).SUBUNIT Interacts with XKR4; interacts with the processed form of XKR4, which is cleaved by caspase.INTERACTION Localizes to site of double-strand breaks.SUBCELLULAR LOCATION Translocates from the nucleus to the cytoplasm following cleavage by caspase-3 (CASP3).ALTERNATIVE PRODUCTS Widely expressed.PTM Phosphorylated by PRKDC at the C-terminus in response to DNA damage; Ser-260 and Ser-320 constitute the main phosphorylation sites (PubMed:12547193, PubMed:14599745, PubMed:15177042, PubMed:26666690, PubMed:28500754, PubMed:30247612, PubMed:9430729). Phosphorylations 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 (PubMed:22228831, PubMed:28500754). Phosphorylation by PRKDC does not prevent interaction with NHEJ1/XLF but disrupts ability to bridge DNA and promotes detachment from DNA (PubMed:22228831, PubMed:28500754). Phosphorylation at Ser-327 and Ser-328 by PRKDC promotes recognition by the SCF(FBXW7) complex and subsequent ubiquitination via 'Lys-63'-linked ubiquitin (PubMed:26774286). Phosphorylation at Thr-233 by CK2 promotes interaction with PNKP; regulating PNKP activity and localization to DNA damage sites (PubMed:15385968, PubMed:20852255, PubMed:28453785). Phosphorylation by CK2 promotes interaction with APTX (PubMed:15380105).PTM Ubiquitinated at Lys-296 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-327 and Ser-328 by PRKDC, and 'Lys-63'-linked ubiquitination facilitates DNA non-homologous end joining (NHEJ) by enhancing association with XRCC5/Ku80 and XRCC6/Ku70 (PubMed:26774286). Monoubiquitinated (PubMed:16412978).PTM Undergoes proteolytic processing by caspase-3 (CASP3) (Probable) (PubMed:33725486). 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 (PubMed:33725486).DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the XRCC4-XLF family. XRCC4 subfamily.CAUTION Sumoylation at Lys-210 was initially reported to regulate nuclear localization and recombination efficiency of XRCC4 (PubMed:16478998). This result is however not confirmed by another study (PubMed:25934149).
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