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Description:
DNA ligase 4 (EC 6.5.1.1) (DNA ligase IV) (Polydeoxyribonucleotidesynthase [ATP] 4).
Molecular weight: 10397
View which proteins in this organism that is involved with DNA Repair;
classified after biological processes (using data from the GOA project):
single strand break repair( GO:0000012 ) DNA repair( GO:0006281 )
Important dates:
01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
07-FEB-2006, sequence version 2.
07-MAR-2006, entry version 59.
Phylogenetic order:
Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Catarrhini Hominidae Homo.
To calculate the pI (Isoelectric point - the pH where a protein has a neutral charge),
go to this page and enter the protein ID (e.g 3MG_ECOLI): http://us.expasy.org/tools/pi_tool.html
Links to references in other databases for protein DNL4_HUMAN:
| Database | Pointer | Add. info#1 | Add. info#2 |
| EMBL | X83441 | CAA58467.1 | ALT_INIT |
| EMBL | AF479264 | AAL77435.1 | ALT_INIT |
| EMBL | AL157762 | CAH70629.1 | - |
| EMBL | BC037491 | AAH37491.1 | - |
| PIR | I37079 | I37079. | |
| PDB | 1IK9 | X-ray | C=681-717. |
| Ensembl | ENSG00000174405 | Homo sapiens.1 | |
| HGNC | HGNC:6601 | LIG4.1 | |
| MIM | 601837 | gene. | |
| MIM | 606593 | phenotype. | |
| Reactome | P49917 | -.1 | |
| GO | GO:0005634 | C:nucleus | TAS. |
| GO | GO:0003677 | F:DNA binding | TAS. |
| GO | GO:0003910 | F:DNA ligase (ATP) activity | TAS. |
| GO | GO:0000012 | P:single strand break repair | TAS. |
| PROSITE | PS50172 | BRCT | 2. |
| PROSITE | PS00697 | DNA_LIGASE_A1 | 1. |
| PROSITE | PS00333 | DNA_LIGASE_A2 | 1. |
| PROSITE | PS50160 | DNA_LIGASE_A3 | 1. |
Keywords:
3D-structure; ATP-binding; Cell cycle; Cell division; Direct protein sequencing; Disease mutation; DNA damage; DNA recombination; DNA repair; DNA replication; Ligase; Nuclear protein; Nucleotide-binding; Polymorphism; Repeat.
References:
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Prostate;
RX MEDLINE=95280920; PubMed=7760816;
RA Wei Y.-F., Robins P., Carter K., Caldecott K., Pappin D.J.C.,
RA Yu G.-L., Wang R.-P., Shell B.K., Nash R.A., Schar P., Barnes D.E.,
RA Haseltine W.A., Lindahl T.;
RT "Molecular cloning and expression of human cDNAs encoding a novel DNA
RT ligase IV and DNA ligase III, an enzyme active in DNA repair and
RT recombination.";
RL Mol. Cell. Biol. 15:3206-3216(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-231 AND THR-857.
RA Rieder M.J., Braun A.C., Montoya M.A., Chung M.-W., Nguyen C.P.,
RA Nguyen D.A., Livingston R.J., Poel C.L., Robertson P.D.,
RA Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.;
RT "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department
RT of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899;
RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G.,
RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D.,
RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K.,
RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F.,
RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L.,
RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E.,
RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C.,
RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J.,
RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H.,
RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W.,
RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A.,
RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A.,
RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G.,
RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C.,
RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M.,
RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E.,
RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.;
RT "Generation and initial analysis of more than 15,000 full-length human
RT and mouse cDNA sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002).
RN [5]
RP CHARACTERIZATION.
RX MEDLINE=96394565; PubMed=8798671; DOI=10.1074/jbc.271.39.24257;
RA Robins P., Lindahl T.;
RT "DNA ligase IV from HeLa cell nuclei.";
RL J. Biol. Chem. 271:24257-24261(1996).
RN [6]
RP FUNCTION, AND INTERACTION WITH XRCC4.
RX MEDLINE=99026597; PubMed=9809069; DOI=10.1016/S1097-2765(00)80147-1;
RA Grawunder U., Zimmer D., Fugmann S., Schwarz K., Lieber M.R.;
RT "DNA ligase IV is essential for V(D)J recombination and DNA double-
RT strand break repair in human precursor lymphocytes.";
RL Mol. Cell 2:477-484(1998).
RN [7]
RP INTERACTION WITH XRCC4.
RX PubMed=9259561; DOI=10.1016/S0960-9822(06)00258-2;
RA Critchlow S.E., Bowater R.P., Jackson S.P.;
RT "Mammalian DNA double-strand break repair protein XRCC4 interacts with
RT DNA ligase IV.";
RL Curr. Biol. 7:588-598(1997).
RN [8]
RP FUNCTION, AND INTERACTIONS WITH XRCC4; G22P1; G22P2 AND PRKDC.
RX PubMed=10854421; DOI=10.1074/jbc.M000491200;
RA Chen L., Trujillo K., Sung P., Tomkinson A.E.;
RT "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the
RT DNA-dependent protein kinase.";
RL J. Biol. Chem. 275:26196-26205(2000).
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH G22P1; G22P2 AND PRKDC.
RX MEDLINE=22435910; PubMed=12547193; DOI=10.1016/S0022-2836(02)01328-1;
RA Calsou P., Delteil C., Frit P., Drouet J., Salles B.;
RT "Coordinated assembly of Ku and p460 subunits of the DNA-dependent
RT protein kinase on DNA ends is necessary for XRCC4-ligase IV
RT recruitment.";
RL J. Mol. Biol. 326:93-103(2003).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 748-784 IN COMPLEX WITH
RP XRCC4.
RX PubMed=11702069; DOI=10.1038/nsb725;
RA Sibanda B.L., Critchlow S.E., Begun J., Pei X.Y., Jackson S.P.,
RA Blundell T.L., Pellegrini L.;
RT "Crystal structure of an Xrcc4-DNA ligase IV complex.";
RL Nat. Struct. Biol. 8:1015-1019(2001).
RN [11]
RP VARIANT LEUKEMIA HIS-278.
RX MEDLINE=99324246; PubMed=10395545; DOI=10.1016/S0960-9822(99)80311-X;
RA Riballo E., Critchlow S.E., Teo S.-H., Doherty A.J., Priestley A.,
RA Broughton B., Kysela B., Beamish H., Plowman N., Arlett C.F.,
RA Lehmann A.R., Jackson S.P., Jeggo P.A.;
RT "Identification of a defect in DNA ligase IV in a radiosensitive
RT leukaemia patient.";
RL Curr. Biol. 9:699-702(1999).
RN [12]
RP CHARACTERIZATION OF VARIANT HIS-278.
RX MEDLINE=21391880; PubMed=11349135; DOI=10.1074/jbc.M103866200;
RA Riballo E., Doherty A.J., Dai Y., Stiff T., Oettinger M.A.,
RA Jeggo P.A., Kysela B.;
RT "Cellular and biochemical impact of a mutation in DNA ligase IV
RT conferring clinical radiosensitivity.";
RL J. Biol. Chem. 276:31124-31132(2001).
RN [13]
RP VARIANTS LIG4 SYNDROME HIS-278 AND GLU-469.
RX MEDLINE=21638666; PubMed=11779494; DOI=10.1016/S1097-2765(01)00408-7;
RA O'Driscoll M., Cerosaletti K.M., Girard P.-M., Dai Y., Stumm M.,
RA Kysela B., Hirsch B., Gennery A., Palmer S.E., Seidel J., Gatti R.A.,
RA Varon R., Oettinger M.A., Neitzel H., Jeggo P.A., Concannon P.;
RT "DNA ligase IV mutations identified in patients exhibiting
RT developmental delay and immunodeficiency.";
RL Mol. Cell 8:1175-1185(2001).
Feature:
CHAIN 1 911 DNA ligase 4.
/FTId=PRO_0000059576.
DOMAIN 654 743 BRCT 1.
DOMAIN 808 911 BRCT 2.
ACT_SITE 273 273 N6-AMP-lysine intermediate (By
similarity).
VARIANT 231 231 P -> S.
/FTId=VAR_018808.
VARIANT 278 278 R -> H (in LIG4 syndrome and leukemia;
impairs activity).
/FTId=VAR_012774.
VARIANT 469 469 G -> E (in LIG4 syndrome).
/FTId=VAR_012775.
VARIANT 539 539 L -> F (in dbSNP:3742212).
/FTId=VAR_016771.
VARIANT 658 658 I -> V (in dbSNP:2232641).
/FTId=VAR_016772.
VARIANT 857 857 A -> T (in dbSNP:2232642).
/FTId=VAR_016773.
CONFLICT 246 246 F -> S (in Ref. 1).
STRAND 757 758
TURN 760 761
STRAND 762 762
STRAND 764 767
HELIX 771 779
TURN 780 780
Comments:
-!- FUNCTION: Efficiently joins single-strand breaks in a double-
stranded polydeoxynucleotide in an ATP-dependent reaction.
Involved in DNA nonhomologous 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: 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.
-!- 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.
-!- SIMILARITY: Belongs to the ATP-dependent DNA ligase family.
-!- SIMILARITY: Contains 2 BRCT domains.
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Sequence length: 911
MAASQTSQTV ASHVPFADLC STLERIQKSK GRAEKIRHFR EFLDSWRKFH DALHKNHKDV
TDSFYPAMRL ILPQLERERM AYGIKETMLA KLYIELLNLP RDGKDALKLL NYRTPTGTHG
DAGDFAMIAY FVLKPRCLQK GSLTIQQVND LLDSIASNNS AKRKDLIKKS LLQLITQSSA
LEQKWLIRMI IKDLKLGVSQ QTIFSVFHND AAELHNVTTD LEKVCRQLHD PSVGLSDISI
TLFSAFKPML AAIADIEHIE KDMKHQSFYI ETKLDGERMQ MHKDGDVYKY FSRNGYNYTD
QFGASPTEGS LTPFIHNAFK ADIQICILDG EMMAYNPNTQ TFMQKGTKFD IKRMVEDSDL
QTCYCVFDVL MVNNKKLGHE TLRKRYEILS SIFTPIPGRI EIVQKTQAHT KNEVIDALNE
AIDKREEGIM VKQPLSIYKP DKRGEGWLKI KPEYVSGLMD ELDILIVGGY WGKGSRGGMM
SHFLCAVAEK PPPGEKPSVF HTLSRVGSGC TMKELYDLGL KLAKYWKPFH RKAPPSSILC
GTEKPEVYIE PCNSVIVQIK AAEIVPSDMY KTGCTLRFPR IEKIRDDKEW HECMTLDDLE
QLRGKASGKL ASKHLYIGGD DEPQEKKRKA APKMKKVIGI IEHLKAPNLT NVNKISNIFE
DVEFCVMSGT DSQPKPDLEN RIAEFGGYIV QNPGPDTYCV IAGSENIRVK NIILSNKHDV
VKPAWLLECF KTKSFVPWQP RFMIHMCPST KEHFAREYDC YGDSYFIDTD LNQLKEVFSG
IKNSNEQTPE EMASLIADLE YRYSWDCSPL SMFRRHTVYL DSYAVINDLS TKNEGTRLAI
KALELRFHGA KVVSCLAEGV SHVIIGEDHS RVADFKAFRR TFKRKFKILK ESWVTDSIDK
CELQEENQYL I