Reviewed, UniProtKB/Swiss-Prot Q13426 (XRCC4_HUMAN)

Names and origin

Protein names

Recommended name:
    DNA repair protein XRCC4
Alternative name(s):
    X-ray repair cross-complementing protein 4

Gene names

Name:

XRCC4

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	336 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. Binds to DNA and to DNA ligase IV (LIG4). The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. Ref.1 Ref.11 Ref.12 Ref.16
Subunit structure	Homodimer and homotetramer in solution. The homodimer associates with LIG4, and the LIG4-XRCC4 complex associates in a DNA-dependent manner with the DNA-PK complex formed by the Ku p70/p86 dimer (G22P1/G22P2) and PRKDC. Seems to interact directly with PRKDC but not with the Ku p70/86 dimer. Interacts with XLF/Cernunnos. Interacts with APTX and APLF. Ref.11 Ref.12 Ref.7 Ref.10 Ref.13 Ref.15 Ref.17 Ref.19
Subcellular location	Nucleus. Ref.7 Ref.18
Tissue specificity	Widely expressed. Ref.1
Post-translational modification	Phosphorylated by PRKDC. The phosphorylation seems not to be necessary for binding to DNA. Phosphorylation by CK2 promotes interaction with APTX. Ref.16 Ref.7 Ref.15 Ref.8 Ref.9 Ref.14 Ref.20 Monoubiquitinated. Sumoylation at Lys-210 is required for nuclear localization and recombination efficiency. Has no effect on ubiquitination.
Sequence similarities	Belongs to the XRCC4 family.

Ontologies

Keywords
Biological process	DNA damage DNA recombination DNA repair
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Coiled coil
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	DNA ligation during DNA repair Inferred from direct assay. Source: UniProtKB double-strand break repair via nonhomologous end joining Ref.17 Inferred from direct assay. Source: UniProtKB initiation of viral infection Inferred from Experiment. Source: Reactome positive regulation of ligase activity Ref.10 Inferred from direct assay. Source: UniProtKB provirus integration Inferred from Experiment. Source: Reactome response to X-ray Ref.10 Inferred from direct assay. Source: UniProtKB
Cellular component	DNA ligase IV complex Ref.10 Inferred from direct assay. Source: UniProtKB DNA-dependent protein kinase-DNA ligase 4 complex Inferred from direct assay. Source: MGI cytosol Ref.7 Inferred from direct assay. Source: UniProtKB
Molecular function	DNA binding Ref.7 Inferred from electronic annotation. Source: InterPro protein C-terminus binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BIN1	O00499	3	EBI-717592,EBI-719094
NHEJ1	Q9H9Q4	3	EBI-717592,EBI-847807
PNKP	Q96T60	1	EBI-717592,EBI-1045072

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q13426-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q13426-2)

The sequence of this isoform differs from the canonical sequence as follows:
     298-300: NSR → K

Isoform 3 (identifier: Q13426-3)

The sequence of this isoform differs from the canonical sequence as follows:
     298-336: NSRPDSSLPETSKKEHISAENMSLETLRNSSPEDLFDEI → KGRKKETSEKEAV

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 336

336

DNA repair protein XRCC4

PRO_0000066047

Regions

Region

180 – 213

34

Interacts with LIG4

Coiled coil

131 – 165

35

Potential

Coiled coil

184 – 212

29

Potential

Amino acid modifications

Modified residue

260

1

Phosphoserine; by PRKDC Ref.9

Modified residue

320

1

Phosphoserine; by PRKDC Ref.9

Modified residue

327

1

Phosphoserine Ref.20

Modified residue

328

1

Phosphoserine Ref.20

Cross-link

210

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.18

Natural variations

Alternative sequence

298 – 336

39

NSRPD…LFDEI → KGRKKETSEKEAV in isoform 3.

VSP_009474

Alternative sequence

298 – 300

3

NSR → K in isoform 2.

VSP_009473

Natural variant

12

1

S → C: dbSNP rs28383138. Ref.5

VAR_022310

Natural variant

56

1

A → T: dbSNP rs28383151. Ref.5

VAR_022311

Natural variant

134

1

I → T: dbSNP rs28360135. Ref.5

VAR_022312

Natural variant

142

1

E → Q: dbSNP rs28360136. Ref.5

VAR_022313

Natural variant

240

1

Q → P: dbSNP rs2974446.

VAR_017810

Natural variant

247

1

A → S: dbSNP rs3734091. Ref.5

VAR_017811

Experimental info

Mutagenesis

140

1

K → R: No change in sumoylation. Ref.18

Mutagenesis

210

1

K → R: Abolishes sumoylation. No nuclear location. 5-fold decrease in recombination efficiency. Ref.18

Secondary structure

1

.

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336

Helix Strand Turn

Details...

Beta strand

2 – 10

9

Beta strand

13 – 26

14

Helix

28 – 30

3

Beta strand

31 – 37

7

Beta strand

42 – 48

7

Helix

49 – 58

10

Helix

63 – 74

12

Beta strand

84 – 88

5

Turn

90 – 92

3

Beta strand

94 – 100

7

Beta strand

105 – 112

8

Helix

119 – 210

92

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 2004. Version 2. Checksum: BE5FB99153479A4E	FASTA	336	38,287
	10 20 30 40 50 60 MERKISRIHL VSEPSITHFL QVSWEKTLES GFVITLTDGH SAWTGTVSES EISQEADDMA 70 80 90 100 110 120 MEKGKYVGEL RKALLSGAGP ADVYTFNFSK ESCYFFFEKN LKDVSFRLGS FNLEKVENPA 130 140 150 160 170 180 EVIRELICYC LDTIAENQAK NEHLQKENER LLRDWNDVQG RFEKCVSAKE ALETDLYKRF 190 200 210 220 230 240 ILVLNEKKTK IRSLHNKLLN AAQEREKDIK QEGETAICSE MTADRDPVYD ESTDEESENQ 250 260 270 280 290 300 TDLSGLASAA VSKDDSIISS LDVTDIAPSR KRRQRMQRNL GTEPKMAPQE NQLQEKENSR 310 320 330 PDSSLPETSK KEHISAENMS LETLRNSSPE DLFDEI
	Isoform 2. Checksum: E32CC403854DCE9B	FASTA	334	38,058
	10 20 30 40 50 60 MERKISRIHL VSEPSITHFL QVSWEKTLES GFVITLTDGH SAWTGTVSES EISQEADDMA 70 80 90 100 110 120 MEKGKYVGEL RKALLSGAGP ADVYTFNFSK ESCYFFFEKN LKDVSFRLGS FNLEKVENPA 130 140 150 160 170 180 EVIRELICYC LDTIAENQAK NEHLQKENER LLRDWNDVQG RFEKCVSAKE ALETDLYKRF 190 200 210 220 230 240 ILVLNEKKTK IRSLHNKLLN AAQEREKDIK QEGETAICSE MTADRDPVYD ESTDEESENQ 250 260 270 280 290 300 TDLSGLASAA VSKDDSIISS LDVTDIAPSR KRRQRMQRNL GTEPKMAPQE NQLQEKEKPD 310 320 330 SSLPETSKKE HISAENMSLE TLRNSSPEDL FDEI
	Isoform 3. Checksum: 30B8DCC13C64A548	FASTA	310	35,372
	10 20 30 40 50 60 MERKISRIHL VSEPSITHFL QVSWEKTLES GFVITLTDGH SAWTGTVSES EISQEADDMA 70 80 90 100 110 120 MEKGKYVGEL RKALLSGAGP ADVYTFNFSK ESCYFFFEKN LKDVSFRLGS FNLEKVENPA 130 140 150 160 170 180 EVIRELICYC LDTIAENQAK NEHLQKENER LLRDWNDVQG RFEKCVSAKE ALETDLYKRF 190 200 210 220 230 240 ILVLNEKKTK IRSLHNKLLN AAQEREKDIK QEGETAICSE MTADRDPVYD ESTDEESENQ 250 260 270 280 290 300 TDLSGLASAA VSKDDSIISS LDVTDIAPSR KRRQRMQRNL GTEPKMAPQE NQLQEKEKGR 310 KKETSEKEAV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination." Li Z., Otevrel T., Gao Y., Cheng H.L., Seed B., Stamato T.D., Taccioli G.E., Alt F.W. Cell 83:1079-1089(1995) [PubMed: 8548796] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY.
[2]	"The genomic structure of the human XRCC4 gene." Fugmann S.D., Schwarz K. Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Human lymphoblastoid cell line TK-6 lacking in a novel compornent involved in V(D)J recombination." Tatsumi K. Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
[5]	NIEHS SNPs program Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CYS-12; THR-56; THR-134; GLN-142 AND SER-247.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Tissue: Bone marrow.
[7]	"Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV." Critchlow S.E., Bowater R.P., Jackson S.P. Curr. Biol. 7:588-598(1997) [PubMed: 9259561] [Abstract] Cited for: INTERACTION WITH LIG4, PHOSPHORYLATION, SUBCELLULAR LOCATION.
[8]	"The XRCC4 gene product is a target for and interacts with the DNA-dependent protein kinase." Leber R., Wise T.W., Mizuta R., Meek K. J. Biol. Chem. 273:1794-1801(1998) [PubMed: 9430729] [Abstract] Cited for: PHOSPHORYLATION BY PRKDC.
[9]	"Identification of DNA-PKcs phosphorylation sites in XRCC4 and effects of mutations at these sites on DNA end joining in a cell-free system." Lee K.J., Jovanovic M., Udayakumar D., Bladen C.L., Dynan W.S. DNA Repair 3:267-276(2004) [PubMed: 15177042] [Abstract] Cited for: PHOSPHORYLATION AT SER-260 AND SER-320.
[10]	"Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells." Grawunder U., Wilm M., Wu X., Kulesza P., Wilson T.E., Mann M., Lieber M.R. Nature 388:492-495(1997) [PubMed: 9242410] [Abstract] Cited for: INTERACTION WITH LIG4.
[11]	"Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase." Chen L., Trujillo K., Sung P., Tomkinson A.E. J. Biol. Chem. 275:26196-26205(2000) [PubMed: 10854421] [Abstract] Cited for: FUNCTION, INTERACTION WITH LIG4; G22P1; G22P2 AND PRKDC.
[12]	"Ku recruits the XRCC4-ligase IV complex to DNA ends." Nick McElhinny S.A., Snowden C.M., McCarville J., Ramsden D.A. Mol. Cell. Biol. 20:2996-3003(2000) [PubMed: 10757784] [Abstract] Cited for: FUNCTION, INTERACTION WITH G22P1 AND G22P2.
[13]	"Defining interactions between DNA-PK and ligase IV/XRCC4." Hsu H.-L., Yannone S.M., Chen D.J. DNA Repair 1:225-235(2002) [PubMed: 12509254] [Abstract] Cited for: INTERACTION WITH PRKDC.
[14]	"Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment." Calsou P., Delteil C., Frit P., Drouet J., Salles B. J. Mol. Biol. 326:93-103(2003) [PubMed: 12547193] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH G22P1; G22P2 AND PRKDC, PHOSPHORYLATION.
[15]	"The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4." Clements P.M., Breslin C., Deeks E.D., Byrd P.J., Ju L., Bieganowski P., Brenner C., Moreira M.-C., Taylor A.M.R., Caldecott K.W. DNA Repair 3:1493-1502(2004) [PubMed: 15380105] [Abstract] Cited for: INTERACTION WITH APTX, PHOSPHORYLATION.
[16]	"Monoubiquitination of the nonhomologous end joining protein XRCC4." Foster R.E., Nnakwe C., Woo L., Frank K.M. Biochem. Biophys. Res. Commun. 341:175-183(2006) [PubMed: 16412978] [Abstract] Cited for: MONOUBIQUITINATION, PHOSPHORYLATION, FUNCTION.
[17]	"XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining." Ahnesorg P., Smith P., Jackson S.P. Cell 124:301-313(2006) [PubMed: 16439205] [Abstract] Cited for: INTERACTION WITH XLF.
[18]	"SUMO modification of human XRCC4 regulates its localization and function in DNA double-strand break repair." Yurchenko V., Xue Z., Sadofsky M.J. Mol. Cell. Biol. 26:1786-1794(2006) [PubMed: 16478998] [Abstract] Cited for: SUMOYLATION AT LYS-210, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-140 AND LYS-210.
[19]	"APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks." Iles N., Rulten S., El-Khamisy S.F., Caldecott K.W. Mol. Cell. Biol. 27:3793-3803(2007) [PubMed: 17353262] [Abstract] Cited for: INTERACTION WITH APLF.
[20]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-327 AND SER-328, MASS SPECTROMETRY.
[21]	"Crystal structure of an Xrcc4-DNA ligase IV complex." Sibanda B.L., Critchlow S.E., Begun J., Pei X.Y., Jackson S.P., Blundell T.L., Pellegrini L. Nat. Struct. Biol. 8:1015-1019(2001) [PubMed: 11702069] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-113 IN COMPLEX WITH LIG4.
[22]	"Tetramerization and DNA ligase IV interaction of the DNA double-strand break repair protein XRCC4 are mutually exclusive." Modesti M., Junop M.S., Ghirlando R., van de Rakt M., Gellert M., Yang W., Kanaar R. J. Mol. Biol. 334:215-228(2003) [PubMed: 14607114] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 1-203.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

U40622 mRNA. Translation: AAC50339.1.
AF055285 , AF055279, AF055280, AF055281, AF055282, AF055283, AF055284 Genomic DNA. Translation: AAD47297.1.
AF055285 , AF055279, AF055280, AF055281, AF055282, AF055283, AF055284 Genomic DNA. Translation: AAD47298.1.
AB017445 mRNA. Translation: BAB20668.1.
BT007216 mRNA. Translation: AAP35880.1.
AY940097 Genomic DNA. Translation: AAX14046.1.
BC005259 mRNA. Translation: AAH05259.1.
BC016314 mRNA. Translation: AAH16314.1.

IPI

IPI00007672.
IPI00019678.
IPI00401064.

RefSeq

NP_003392.1.
NP_071801.1.
NP_072044.1.

UniGene

Hs.567359

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FU1	X-ray	2.70	A/B	1-203	[»]
1IK9	X-ray	2.30	A/B	1-213	[»]

DisProt

DP00152.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q13426. 12 interactions.

PTM databases

PhosphoSite

Q13426.

Proteomic databases

PRIDE

Q13426.

Genome annotation databases

Ensembl

ENSG00000152422. Homo sapiens. [Contig view]

GeneID

7518.

KEGG

hsa:7518.

UCSC

uc003kia.1. human.
uc003kib.1. human.
uc003kic.1. human.

Organism-specific databases

GeneCards

GC05P082409.

H-InvDB

HIX0005011.

HGNC

HGNC:12831. XRCC4.

HPA

HPA006801.

MIM

194363. gene.

PharmGKB

PA37423.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q13426.

HOVERGEN

Q13426.

OMA

Q13426. SFRLGSF.

Enzyme and pathway databases

Reactome

REACT_216. DNA Repair.
REACT_6185. HIV Infection.

Gene expression databases

ArrayExpress

Q13426.

Bgee

Q13426.

CleanEx

HS_XRCC4.

GermOnline

ENSG00000152422. Homo sapiens.

Family and domain databases

InterPro

IPR010585. XRCC4.
IPR014751. XRCC4_C.
IPR009089. XRCC4_N.
[Graphical view]

Gene3D

G3DSA:1.20.5.370. XRCC4_C. 1 hit.
G3DSA:2.170.210.10. XRCC4_N. 1 hit.

Pfam

PF06632. XRCC4. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

29423.

PMAP-CutDB

Q13426.

SOURCE

Search...

Entry information

Entry name

XRCC4_HUMAN

Accession

Primary (citable) accession number: Q13426
Secondary accession number(s): Q9BS72, Q9UP94

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 1, 2004
Last sequence update:	March 1, 2004
Last modified:	July 7, 2009
This is version 81 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)