XRCC4_CRIGR
ID XRCC4_CRIGR Reviewed; 327 AA.
AC G3HKI1;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 29-SEP-2021, sequence version 2.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=DNA repair protein XRCC4 {ECO:0000305};
DE AltName: Full=X-ray repair cross-complementing protein 4 {ECO:0000303|PubMed:18093953};
DE Contains:
DE RecName: Full=Protein XRCC4, C-terminus {ECO:0000250|UniProtKB:Q13426};
DE Short=XRCC4/C {ECO:0000250|UniProtKB:Q13426};
GN Name=XRCC4 {ECO:0000303|PubMed:18093953};
GN ORFNames=I79_011207 {ECO:0000303|PubMed:21804562};
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=21804562; DOI=10.1038/nbt.1932;
RA Xu X., Nagarajan H., Lewis N.E., Pan S., Cai Z., Liu X., Chen W., Xie M.,
RA Wang W., Hammond S., Andersen M.R., Neff N., Passarelli B., Koh W.,
RA Fan H.C., Wang J., Gui Y., Lee K.H., Betenbaugh M.J., Quake S.R.,
RA Famili I., Palsson B.O., Wang J.;
RT "The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line.";
RL Nat. Biotechnol. 29:735-741(2011).
RN [2]
RP FUNCTION.
RX PubMed=18093953; DOI=10.1073/pnas.0708541104;
RA Guirouilh-Barbat J., Rass E., Plo I., Bertrand P., Lopez B.S.;
RT "Defects in XRCC4 and KU80 differentially affect the joining of distal
RT nonhomologous ends.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:20902-20907(2007).
RN [3]
RP INTERACTION WITH LIG4.
RX PubMed=10047779; DOI=10.1016/s0921-8777(98)00063-9;
RA Bryans M., Valenzano M.C., Stamato T.D.;
RT "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization
RT by XRCC4.";
RL Mutat. Res. 433:53-58(1999).
CC -!- FUNCTION: [DNA repair protein XRCC4]: DNA non-homologous end joining
CC (NHEJ) core factor, required for double-strand break repair and V(D)J
CC recombination (PubMed:18093953). Acts as a scaffold protein that
CC regulates recruitment of other proteins to DNA double-strand breaks
CC (DSBs). Associates with NHEJ1/XLF to form alternating helical filaments
CC that bridge DNA and act like a bandage, holding together the broken DNA
CC until it is repaired. The XRCC4-NHEJ1/XLF subcomplex binds to the DNA
CC fragments of a DSB in a highly diffusive manner and robustly bridges
CC two independent DNA molecules, holding the broken DNA fragments in
CC close proximity to one other. The mobility of the bridges ensures that
CC the ends remain accessible for further processing by other repair
CC factors. Plays a key role in the NHEJ ligation step of the broken DNA
CC during DSB repair via direct interaction with DNA ligase IV (LIG4): the
CC LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is
CC completed. XRCC4 stabilizes LIG4, regulates its subcellular
CC localization and enhances LIG4's joining activity. Binding of the LIG4-
CC XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-
CC dependent protein kinase complex DNA-PK to these DNA ends. Promotes
CC displacement of PNKP from processed strand break termini (By
CC similarity). {ECO:0000250|UniProtKB:Q13426,
CC ECO:0000269|PubMed:18093953}.
CC -!- FUNCTION: [Protein XRCC4, C-terminus]: Acts as an activator of the
CC phospholipid scramblase activity of XKR4. This form, which is generated
CC upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and
CC interacts with XKR4, thereby promoting phosphatidylserine scramblase
CC activity of XKR4 and leading to phosphatidylserine exposure on
CC apoptotic cell surface. {ECO:0000250|UniProtKB:Q13426}.
CC -!- SUBUNIT: [DNA repair protein XRCC4]: Homodimer and homotetramer in
CC solution (By similarity). Interacts with NHEJ1/XLF; the interaction is
CC direct and is mediated via a head-to-head interaction between N-
CC terminal head regions (By similarity). Interacts with LIG4; the LIG4-
CC XRCC4 subcomplex has a 1:2 stoichiometry and XRCC4 is required for LIG4
CC stability (PubMed:10047779). Component of the core long-range non-
CC homologous end joining (NHEJ) complex (also named DNA-PK complex)
CC composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF
CC (By similarity). Additional component of the NHEJ complex includes PAXX
CC (By similarity). Following autophosphorylation, PRKDC dissociates from
CC DNA, leading to formation of the short-range NHEJ complex, composed of
CC LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (By similarity).
CC Interacts with PRKDC; the interaction is direct (By similarity).
CC Interacts with XRCC6/Ku70; the interaction is direct (By similarity).
CC Interacts with APTX and APLF (By similarity). Forms a heterotetramer
CC with IFFO1; the interaction involves LIG4-free XRCC4 and leads to the
CC relocalization of IFFO1 to the sites of DNA damage (By similarity).
CC Interacts with PNKP; mainly interacts with PNKP when phosphorylated at
CC Thr-230, but is also able to interact at much lower level with PNKP
CC when not unphosphorylated (By similarity). Interacts with POLL (DNA
CC polymerase lambda) (By similarity). {ECO:0000250|UniProtKB:Q13426,
CC ECO:0000269|PubMed:10047779}.
CC -!- SUBUNIT: [Protein XRCC4, C-terminus]: Interacts with XKR4; interacts
CC with the processed form of XKR4, which is cleaved by caspase.
CC {ECO:0000250|UniProtKB:Q13426}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q13426}.
CC Chromosome {ECO:0000250|UniProtKB:Q13426}. Note=Localizes to site of
CC double-strand breaks. {ECO:0000250|UniProtKB:Q13426}.
CC -!- SUBCELLULAR LOCATION: [Protein XRCC4, C-terminus]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q13426}. Note=Translocates from the nucleus to
CC the cytoplasm following cleavage by caspase-3 (CASP3).
CC {ECO:0000250|UniProtKB:Q13426}.
CC -!- PTM: Phosphorylated by PRKDC at the C-terminus in response to DNA
CC damage; Ser-253 constitutes the main phosphorylation sites.
CC Phosphorylations by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are
CC highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex
CC to bridge DNA. Phosphorylation by PRKDC does not prevent interaction
CC with NHEJ1/XLF but disrupts ability to bridge DNA and promotes
CC detachment from DNA. Phosphorylation at Ser-320 and Ser-321 by PRKDC
CC promotes recognition by the SCF(FBXW7) complex and subsequent
CC ubiquitination via 'Lys-63'-linked ubiquitin. Phosphorylation at Thr-
CC 230 by CK2 promotes interaction with PNKP; regulating PNKP activity and
CC localization to DNA damage sites. Phosphorylation by CK2 promotes
CC interaction with APTX. {ECO:0000250|UniProtKB:Q13426}.
CC -!- PTM: Ubiquitinated at Lys-289 by the SCF(FBXW7) complex via 'Lys-63'-
CC linked ubiquitination, thereby promoting double-strand break repair:
CC the SCF(FBXW7) complex specifically recognizes XRCC4 when
CC phosphorylated at Ser-320 and Ser-321 by PRKDC, and 'Lys-63'-linked
CC ubiquitination facilitates DNA non-homologous end joining (NHEJ) by
CC enhancing association with XRCC5/Ku80 and XRCC6/Ku70.
CC Monoubiquitinated. {ECO:0000250|UniProtKB:Q13426}.
CC -!- PTM: [DNA repair protein XRCC4]: Undergoes proteolytic processing by
CC caspase-3 (CASP3). This generates the protein XRCC4, C-terminus
CC (XRCC4/C), which translocates to the cytoplasm and activates
CC phospholipid scramblase activity of XKR4, thereby promoting
CC phosphatidylserine exposure on apoptotic cell surface.
CC {ECO:0000250|UniProtKB:Q13426}.
CC -!- SIMILARITY: Belongs to the XRCC4-XLF family. XRCC4 subfamily.
CC {ECO:0000305}.
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DR EMBL; JH000462; EGW09548.1; -; Genomic_DNA.
DR RefSeq; XP_007634343.1; XM_007636153.2.
DR RefSeq; XP_007642910.1; XM_007644720.1.
DR SMR; G3HKI1; -.
DR STRING; 10029.XP_007634343.1; -.
DR Ensembl; ENSCGRT00001028642; ENSCGRP00001024396; ENSCGRG00001022340.
DR GeneID; 100768249; -.
DR KEGG; cge:100768249; -.
DR eggNOG; ENOG502QWJA; Eukaryota.
DR GeneTree; ENSGT00390000017079; -.
DR InParanoid; G3HKI1; -.
DR Proteomes; UP000001075; Unassembled WGS sequence.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0051103; P:DNA ligation involved in DNA repair; ISS:UniProtKB.
DR GO; GO:0006310; P:DNA recombination; IEA:UniProtKB-KW.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; ISS:UniProtKB.
DR GO; GO:1905782; P:positive regulation of phosphatidylserine exposure on apoptotic cell surface; ISS:UniProtKB.
DR Gene3D; 1.20.5.370; -; 1.
DR Gene3D; 2.170.210.10; -; 1.
DR InterPro; IPR010585; DNA_repair_prot_XRCC4.
DR InterPro; IPR014751; XRCC4-like_C.
DR InterPro; IPR038051; XRCC4-like_N_sf.
DR InterPro; IPR009089; XRCC4_N_sf.
DR PANTHER; PTHR28559; PTHR28559; 1.
DR Pfam; PF06632; XRCC4; 1.
DR SUPFAM; SSF50809; SSF50809; 1.
PE 1: Evidence at protein level;
KW Chromosome; Coiled coil; Cytoplasm; DNA damage; DNA recombination;
KW DNA repair; DNA-binding; Isopeptide bond; Nucleus; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1..327
FT /note="DNA repair protein XRCC4"
FT /id="PRO_0000453298"
FT CHAIN 259..327
FT /note="Protein XRCC4, C-terminus"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT /id="PRO_0000453299"
FT REGION 1..211
FT /note="Interaction with IFFO1"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT REGION 179..211
FT /note="Interaction with LIG4"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT REGION 179..210
FT /note="Interaction with LIG4"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT REGION 255..327
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 133..153
FT /evidence="ECO:0000255"
FT COILED 183..213
FT /evidence="ECO:0000255"
FT MOTIF 263..268
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT COMPBIAS 277..292
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 295..309
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 258..259
FT /note="Cleavage; by caspase-3"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 53
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 192
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 226
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 229
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 230
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 249
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 253
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 294
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 295
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 308
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 313
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT MOD_RES 316
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q924T3"
FT MOD_RES 320
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q924T3"
FT MOD_RES 321
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q924T3"
FT CROSSLNK 208
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
FT CROSSLNK 289
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q13426"
SQ SEQUENCE 327 AA; 37183 MW; F3FF05544FF19AC0 CRC64;
MERKVSRISL ASEPNITYFL QVSWEETVGS GFVITLTDGH SAWTATVSES EISQEADDMA
MEKEKYADEL RKALVSGSGS DTYKFIFSRE SCHFSLEKEL KDVSFRLGSF NLDKVPNSTE
VIRELICYCL DTIAEKQAKN EHLQKENDRL LRDWNDVQGR FEKCVIAKEA LEADLYQRFI
LVLNEKKTKI RSLHKLLDEI QQLEKNLKPE RETKCSEKTT DQDAIYDGST DEEAGASVLA
EAAVCKEDSL FSSPDVTDIA PSRKRRHHMQ KNLGTEPKMA PQEQQLQGKE RLASSLPHTL
KEEHEHTSAG NMSLETLRNS SPEDIFD
