Reviewed, UniProtKB/Swiss-Prot P49917 (DNLI4_HUMAN)

Names and origin

Protein names

Recommended name:
    DNA ligase 4
    EC=6.5.1.1
Alternative name(s):
    DNA ligase IV
    Polydeoxyribonucleotide synthase [ATP] 4

Gene names

Name:

LIG4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	911 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Efficiently joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. 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.
Catalytic activity	ATP + (deoxyribonucleotide)(n) + (deoxyribonucleotide)(m) = AMP + diphosphate + (deoxyribonucleotide)(n+m).
Subunit structure	Binds to XRCC4. The LIG4-XRCC4 complex has probably a 1:2 stoichiometry. The LIG4-XRCC4 heteromer associates in a DNA-dependent manner with the DNA-dependent protein kinase complex DNA-PK, formed by the Ku p70/p86 dimer (G22P1/G22P2) and PRKDC.
Subcellular location	Nucleus.
Tissue specificity	Testis, thymus, prostate and heart.
Involvement in disease	Defects in LIG4 are the cause of LIG4 syndrome [MIM:606593]. This disease is characterized by immunodeficiency and developmental and growth delay. Patients display unusual facial features, microcephaly, growth and/or developmental delay, pancytopenia, and various skin abnormalities. Defects in LIG4 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation (RSSCID) [MIM:602450]. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects in the DNA repair machinery necessary for coding joint formation and the completion of V(D)J recombination. A subset of cells from such patients show increased radiosensitivity.
Sequence similarities	Belongs to the ATP-dependent DNA ligase family. Contains 2 BRCT domains.

Ontologies

Keywords
Biological process	Cell cycle Cell division DNA damage DNA recombination DNA repair DNA replication
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation SCID
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding
Molecular function	Ligase
PTM	Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	DNA ligation during DNA recombination Inferred from sequence or structural similarity. Source: UniProtKB DNA ligation during DNA repair Inferred from direct assay. Source: UniProtKB DNA replication Inferred from electronic annotation. Source: InterPro T cell differentiation in the thymus Inferred from sequence or structural similarity. Source: UniProtKB T cell receptor V(D)J recombination Inferred from sequence or structural similarity. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cell division Inferred from electronic annotation. Source: UniProtKB-KW central nervous system development Inferred from sequence or structural similarity. Source: UniProtKB chromosome organization Inferred from sequence or structural similarity. Source: UniProtKB double-strand break repair via nonhomologous end joining Ref.6 Inferred from direct assay. Source: UniProtKB in utero embryonic development Inferred from sequence or structural similarity. Source: UniProtKB initiation of viral infection Inferred from Experiment. Source: Reactome isotype switching Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of neuron apoptosis Inferred from sequence or structural similarity. Source: UniProtKB nucleotide-excision repair, DNA gap filling Inferred from direct assay. Source: UniProtKB positive regulation of fibroblast proliferation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of neurogenesis Inferred from sequence or structural similarity. Source: UniProtKB pro-B cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB provirus integration Inferred from Experiment. Source: Reactome response to X-ray Ref.6 Inferred from mutant phenotype. Source: UniProtKB response to gamma radiation Inferred from sequence or structural similarity. Source: UniProtKB single strand break repair Ref.5 Inferred from direct assay. Source: UniProtKB somatic stem cell maintenance Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	DNA ligase IV complex Ref.6 Inferred from mutant phenotype. Source: UniProtKB DNA-dependent protein kinase complex Inferred from sequence or structural similarity. Source: UniProtKB condensed chromosome Inferred from direct assay. Source: UniProtKB cytoplasm Inferred from direct assay. Source: HPA focal adhesion Inferred from direct assay. Source: HPA
Molecular function	ATP binding Ref.5 Inferred by curator. Source: UniProtKB DNA binding Ref.5 Inferred from direct assay. Source: UniProtKB DNA ligase (ATP) activity Ref.5 Inferred from direct assay. Source: UniProtKB protein C-terminus binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
NHEJ1	Q9H9Q4	4	EBI-847896,EBI-847807
PNKP	Q96T60	1	EBI-847896,EBI-1045072

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 911

911

DNA ligase 4

PRO_0000059576

Regions

Domain

654 – 743

90

BRCT 1

Domain

808 – 911

104

BRCT 2

Sites

Active site

273

1

N6-AMP-lysine intermediate By similarity

Amino acid modifications

Modified residue

347

1

Phosphothreonine

Natural variations

Natural variant

3

1

A → V Associated with resistance to multiple myeloma. dbSNP rs1805389.

VAR_029352

Natural variant

9

1

T → I Associated with resistance to multiple myeloma. dbSNP rs1805388.

VAR_033884

Natural variant

62

1

D → H: dbSNP rs3093763.

VAR_029353

Natural variant

231

1

P → S: dbSNP rs3093765.

VAR_018808

Natural variant

278

1

R → H in LIG4 syndrome and leukemia; impairs activity.

VAR_012774

Natural variant

433

1

Missing in RS-SCID.

VAR_044123

Natural variant

461

1

E → G: dbSNP rs2232640.

VAR_044124

Natural variant

469

1

G → E in LIG4 syndrome.

VAR_012775

Natural variant

539

1

L → F: dbSNP rs3742212.

VAR_016771

Natural variant

658

1

I → V: dbSNP rs2232641.

VAR_016772

Natural variant

857

1

A → T: dbSNP rs2232642.

VAR_016773

Experimental info

Sequence conflict

246

1

F → S in CAA58467. Ref.1

Secondary structure

1

.

.

.

.

.

.

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.

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.

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.

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.

.

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.

.

911

Helix Strand Turn

Details...

Turn

658 – 661

4

Beta strand

662 – 668

7

Beta strand

671 – 673

3

Helix

675 – 684

10

Beta strand

687 – 692

6

Beta strand

700 – 704

5

Helix

707 – 715

9

Helix

723 – 732

10

Turn

740 – 742

3

Beta strand

743 – 745

3

Turn

748 – 750

3

Beta strand

764 – 767

4

Helix

771 – 779

9

Sequences

	Sequence		Length	Mass (Da)
	P49917-1 [UniParc]. Last modified February 7, 2006. Version 2. Checksum: 2122813E1EFA63B9	FASTA	911	103,971
	10 20 30 40 50 60 MAASQTSQTV ASHVPFADLC STLERIQKSK GRAEKIRHFR EFLDSWRKFH DALHKNHKDV 70 80 90 100 110 120 TDSFYPAMRL ILPQLERERM AYGIKETMLA KLYIELLNLP RDGKDALKLL NYRTPTGTHG 130 140 150 160 170 180 DAGDFAMIAY FVLKPRCLQK GSLTIQQVND LLDSIASNNS AKRKDLIKKS LLQLITQSSA 190 200 210 220 230 240 LEQKWLIRMI IKDLKLGVSQ QTIFSVFHND AAELHNVTTD LEKVCRQLHD PSVGLSDISI 250 260 270 280 290 300 TLFSAFKPML AAIADIEHIE KDMKHQSFYI ETKLDGERMQ MHKDGDVYKY FSRNGYNYTD 310 320 330 340 350 360 QFGASPTEGS LTPFIHNAFK ADIQICILDG EMMAYNPNTQ TFMQKGTKFD IKRMVEDSDL 370 380 390 400 410 420 QTCYCVFDVL MVNNKKLGHE TLRKRYEILS SIFTPIPGRI EIVQKTQAHT KNEVIDALNE 430 440 450 460 470 480 AIDKREEGIM VKQPLSIYKP DKRGEGWLKI KPEYVSGLMD ELDILIVGGY WGKGSRGGMM 490 500 510 520 530 540 SHFLCAVAEK PPPGEKPSVF HTLSRVGSGC TMKELYDLGL KLAKYWKPFH RKAPPSSILC 550 560 570 580 590 600 GTEKPEVYIE PCNSVIVQIK AAEIVPSDMY KTGCTLRFPR IEKIRDDKEW HECMTLDDLE 610 620 630 640 650 660 QLRGKASGKL ASKHLYIGGD DEPQEKKRKA APKMKKVIGI IEHLKAPNLT NVNKISNIFE 670 680 690 700 710 720 DVEFCVMSGT DSQPKPDLEN RIAEFGGYIV QNPGPDTYCV IAGSENIRVK NIILSNKHDV 730 740 750 760 770 780 VKPAWLLECF KTKSFVPWQP RFMIHMCPST KEHFAREYDC YGDSYFIDTD LNQLKEVFSG 790 800 810 820 830 840 IKNSNEQTPE EMASLIADLE YRYSWDCSPL SMFRRHTVYL DSYAVINDLS TKNEGTRLAI 850 860 870 880 890 900 KALELRFHGA KVVSCLAEGV SHVIIGEDHS RVADFKAFRR TFKRKFKILK ESWVTDSIDK 910 CELQEENQYL I

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination." Wei Y.-F., Robins P., Carter K., Caldecott K., Pappin D.J.C., Yu G.-L., Wang R.-P., Shell B.K., Nash R.A., Schar P., Barnes D.E., Haseltine W.A., Lindahl T. Mol. Cell. Biol. 15:3206-3216(1995) [PubMed: 7760816] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Prostate.
[2]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Braun A.C., Montoya M.A., Chung M.-W., Nguyen C.P., Nguyen D.A., Livingston R.J., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-231 AND THR-857.
[3]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed: 15057823] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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]. Tissue: Brain.
[5]	"DNA ligase IV from HeLa cell nuclei." Robins P., Lindahl T. J. Biol. Chem. 271:24257-24261(1996) [PubMed: 8798671] [Abstract] Cited for: CHARACTERIZATION.
[6]	"DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes." Grawunder U., Zimmer D., Fugmann S., Schwarz K., Lieber M.R. Mol. Cell 2:477-484(1998) [PubMed: 9809069] [Abstract] Cited for: FUNCTION, INTERACTION WITH XRCC4.
[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 XRCC4.
[8]	"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 XRCC4; G22P1; G22P2 AND PRKDC.
[9]	"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.
[10]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-347, MASS SPECTROMETRY.
[11]	"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 748-784 IN COMPLEX WITH XRCC4.
[12]	"Solution structure of the first BRCT domain of human DNA ligase IV." RIKEN structural genomics initiative (RSGI) Submitted (DEC-2006) to the PDB data bank Cited for: STRUCTURE BY NMR OF 654-759.
[13]	"Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient." Riballo E., Critchlow S.E., Teo S.-H., Doherty A.J., Priestley A., Broughton B.C., Kysela B., Beamish H., Plowman N., Arlett C.F., Lehmann A.R., Jackson S.P., Jeggo P.A. Curr. Biol. 9:699-702(1999) [PubMed: 10395545] [Abstract] Cited for: VARIANT LEUKEMIA HIS-278.
[14]	"Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity." Riballo E., Doherty A.J., Dai Y., Stiff T., Oettinger M.A., Jeggo P.A., Kysela B. J. Biol. Chem. 276:31124-31132(2001) [PubMed: 11349135] [Abstract] Cited for: CHARACTERIZATION OF VARIANT HIS-278.
[15]	"DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency." O'Driscoll M., Cerosaletti K.M., Girard P.-M., Dai Y., Stumm M., Kysela B., Hirsch B., Gennery A., Palmer S.E., Seidel J., Gatti R.A., Varon R., Oettinger M.A., Neitzel H., Jeggo P.A., Concannon P. Mol. Cell 8:1175-1185(2001) [PubMed: 11779494] [Abstract] Cited for: VARIANTS LIG4 SYNDROME HIS-278 AND GLU-469.
[16]	"Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination." Roddam P.L., Rollinson S., O'Driscoll M., Jeggo P.A., Jack A., Morgan G.J. J. Med. Genet. 39:900-905(2002) [PubMed: 12471202] [Abstract] Cited for: VARIANTS VAL-3 AND ILE-9, ASSOCIATION WITH RESISTANCE TO MULTIPLE MYELOMA.
[17]	"A new type of radiosensitive T-B-NK(+) severe combined immunodeficiency caused by a LIG4 mutation." van der Burg M., van Veelen L.R., Verkaik N.S., Wiegant W.W., Hartwig N.G., Barendregt B.H., Brugmans L., Raams A., Jaspers N.G.J., Zdzienicka M.Z., van Dongen J.J.M., van Gent D.C. J. Clin. Invest. 116:137-145(2006) [PubMed: 16357942] [Abstract] Cited for: VARIANT RS-SCID GLN-433 DEL.
+	Additional computationally mapped references.

Web resources

LIG4base

LIG4 mutation db

Wikipedia

DNA ligase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

X83441 mRNA. Translation: CAA58467.1. Different initiation.
AF479264 Genomic DNA. Translation: AAL77435.1. Different initiation.
AL157762 Genomic DNA. Translation: CAH70629.1.
BC037491 mRNA. Translation: AAH37491.1.

PIR

I37079.

RefSeq

NP_001091738.1.
NP_002303.2.
NP_996820.1.

UniGene

Hs.166091

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IK9	X-ray	2.30	C	748-784	[»]
2E2W	NMR	-	A	654-759	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P49917.

PTM databases

PhosphoSite

P49917.

Polymorphism databases

NIEHS-SNPs

Search...

Genome annotation databases

Ensembl

ENSG00000174405. Homo sapiens. [Contig view]

GeneID

3981.

KEGG

hsa:3981.

Organism-specific databases

H-InvDB

HIX0026564.

HGNC

HGNC:6601. LIG4.

HPA

HPA001334.

MIM