LIG4

Ligase IV, DNA, ATP-dependent
PDB rendering based on 1ik9.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1IK9​, 2E2W​, 3II6​, 3VNN​, 3W1B​, 3W1G​, 3W5O​, 4HTO​, 4HTP​
Identifiers
Symbols	LIG4 ; LIG4S
External IDs	OMIM: 601837 MGI: 1335098 HomoloGene: 1736 GeneCards: LIG4 Gene
EC number	6.5.1.1
Gene ontology Molecular function • DNA binding • DNA ligase activity • DNA ligase (ATP) activity • protein binding • ATP binding • protein C-terminus binding • ligase activity • metal ion binding Cellular component • condensed chromosome • nucleus • nucleoplasm • cytoplasm • plasma membrane • focal adhesion • DNA-dependent protein kinase-DNA ligase 4 complex • DNA ligase IV complex • nonhomologous end joining complex Biological process • single strand break repair • in utero embryonic development • pro-B cell differentiation • DNA ligation • lagging strand elongation • DNA repair • nucleotide-excision repair, DNA gap filling • double-strand break repair • double-strand break repair via nonhomologous end joining • cell cycle • central nervous system development • cell proliferation • response to X-ray • response to gamma radiation • viral process • T cell differentiation in thymus • V(D)J recombination • immunoglobulin V(D)J recombination • T cell receptor V(D)J recombination • somatic stem cell maintenance • negative regulation of neuron apoptotic process • isotype switching • positive regulation of fibroblast proliferation • positive regulation of neurogenesis • DNA ligation involved in DNA recombination • DNA ligation involved in DNA repair • chromosome organization • cell division • neuron apoptotic process • cellular response to lithium ion • DNA biosynthetic process • establishment of integrated proviral latency • double-strand break repair via classical nonhomologous end joining Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3981	319583
Ensembl	ENSG00000174405	ENSMUSG00000049717
UniProt	P49917	Q8BTF7
RefSeq (mRNA)	NM_001098268	NM_176953
RefSeq (protein)	NP_001091738	NP_795927
Location (UCSC)	Chr 13: 108.21 – 108.22 Mb	Chr 8: 9.97 – 9.98 Mb
PubMed search

LIG4 is a human gene that encodes the protein DNA Ligase IV.^[1]

Function

The protein encoded by this gene is an ATP-dependent DNA ligase that joins double-strand breaks during the non-homologous end joining pathway of double-strand break repair. It is also essential for V(D)J recombination. Lig4 forms a complex with XRCC4, and further interacts with the DNA-dependent protein kinase (DNA-PK) and XLF/Cernunnos, which are also required for NHEJ. The crystal structure of the Lig4/XRCC4 complex has been resolved.^[2] Defects in this gene are the cause of LIG4 syndrome. The yeast homolog of Lig4 is Dnl4.

LIG4 Syndrome

In humans, deficiency of DNA ligase 4 results in a clinical condition known as LIG4 syndrome. This syndrome is characterized by cellular radiation sensitivity, growth retardation, developmental delay, microcephaly, facial dysmorphisms, increased disposition to leukemia, variable degrees of immunodeficiency and reduced number of blood cells.^[3][4]

Haematopoietic stem cell aging

Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging.^[5][6] Deficiency of lig4 in pluripotent stem cells impairs Non-homologous end joining (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.^[4] Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging.^[7] The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.^[4][7]

Interactions

LIG4 has been shown to interact with XRCC4 via its BRCT domain.^[8][9] This interaction stabilizes LIG4 protein in cells; cells that are deficient for XRCC4, such as XR-1 cells, have reduced levels of LIG4.^[10]

Mechanism

LIG4 is an ATP-dependent DNA ligase. LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end. Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product. Adenylation of LIG4 is stimulated by XRCC4 and XLF.^[11]

References

1. "Entrez Gene: LIG4 ligase IV, DNA, ATP-dependent".
2. Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (Dec 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. doi:10.1038/nsb725. PMID 11702069.
3. Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, Coakley KM, Detre C, Keszei M, Walter JE, Feldman L, Cheng HL, Poliani PL, Wang JH, Balter BB, Recher M, Andersson EM, Zha S, Giliani S, Terhorst C, Alt FW, Yan CT (Feb 2010). "Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome". Proceedings of the National Academy of Sciences of the United States of America 107 (7): 3024–9. doi:10.1073/pnas.0914865107. PMC 2840307. PMID 20133615.
4. Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama JY, Burks D, Yung S, Singhapol C, Saretzki G, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M (Aug 2013). "A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors". Cell Death and Differentiation 20 (8): 1089–100. doi:10.1038/cdd.2013.44. PMC 3705601. PMID 23722522.
5. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL (Jun 2007). "Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age". Nature 447 (7145): 725–9. doi:10.1038/nature05862. PMID 17554309.
6. Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 ISBN 1604565810 ISBN 978-1604565812
7. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ (Jun 2007). "DNA repair is limiting for haematopoietic stem cells during ageing". Nature 447 (7145): 686–90. doi:10.1038/nature05875. PMID 17554302.
8. Deshpande RA, Wilson TE (Oct 2007). "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair 6 (10): 1507–16. doi:10.1016/j.dnarep.2007.04.014. PMC 2064958. PMID 17567543.
9. Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (Dec 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. doi:10.1038/nsb725. PMID 11702069.
10. Bryans M, Valenzano MC, Stamato TD (Jan 1999). "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4". Mutation Research 433 (1): 53–8. doi:10.1016/s0921-8777(98)00063-9. PMID 10047779.
11. Mahaney BL, Hammel M, Meek K, Tainer JA, Lees-Miller SP (Feb 2013). "XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair". Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire 91 (1): 31–41. doi:10.1139/bcb-2012-0058. PMID 23442139.

Further reading

• Wei YF, Robins P, Carter K, Caldecott K, Pappin DJ, Yu GL, Wang RP, Shell BK, Nash RA, Schär P (Jun 1995). "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". Molecular and Cellular Biology 15 (6): 3206–16. doi:10.1128/mcb.15.6.3206. PMC 230553. PMID 7760816.
• Robins P, Lindahl T (Sep 1996). "DNA ligase IV from HeLa cell nuclei". The Journal of Biological Chemistry 271 (39): 24257–61. doi:10.1074/jbc.271.39.24257. PMID 8798671.
• Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR (Jul 1997). "Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells". Nature 388 (6641): 492–5. doi:10.1038/41358. PMID 9242410.
• Critchlow SE, Bowater RP, Jackson SP (Aug 1997). "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV". Current Biology 7 (8): 588–98. doi:10.1016/S0960-9822(06)00258-2. PMID 9259561.
• Grawunder U, Zimmer D, Lieber MR (Jul 1998). "DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains". Current Biology 8 (15): 873–6. doi:10.1016/S0960-9822(07)00349-1. PMID 9705934.
• Grawunder U, Zimmer D, Fugmann S, Schwarz K, Lieber MR (Oct 1998). "DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes". Molecular Cell 2 (4): 477–84. doi:10.1016/S1097-2765(00)80147-1. PMID 9809069.
• Riballo E, Critchlow SE, Teo SH, Doherty AJ, Priestley A, Broughton B, Kysela B, Beamish H, Plowman N, Arlett CF, Lehmann AR, Jackson SP, Jeggo PA (Jul 1999). "Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient". Current Biology 9 (13): 699–702. doi:10.1016/S0960-9822(99)80311-X. PMID 10395545.
• Kim ST, Lim DS, Canman CE, Kastan MB (Dec 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
• Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA (May 2000). "Ku recruits the XRCC4-ligase IV complex to DNA ends". Molecular and Cellular Biology 20 (9): 2996–3003. doi:10.1128/MCB.20.9.2996-3003.2000. PMC 85565. PMID 10757784.
• Chen L, Trujillo K, Sung P, Tomkinson AE (Aug 2000). "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase". The Journal of Biological Chemistry 275 (34): 26196–205. doi:10.1074/jbc.M000491200. PMID 10854421.
• Lee KJ, Huang J, Takeda Y, Dynan WS (Nov 2000). "DNA ligase IV and XRCC4 form a stable mixed tetramer that functions synergistically with other repair factors in a cell-free end-joining system". The Journal of Biological Chemistry 275 (44): 34787–96. doi:10.1074/jbc.M004011200. PMID 10945980.
• Riballo E, Doherty AJ, Dai Y, Stiff T, Oettinger MA, Jeggo PA, Kysela B (Aug 2001). "Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity". The Journal of Biological Chemistry 276 (33): 31124–32. doi:10.1074/jbc.M103866200. PMID 11349135.
• Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (Dec 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. doi:10.1038/nsb725. PMID 11702069.
• O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P (Dec 2001). "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency". Molecular Cell 8 (6): 1175–85. doi:10.1016/S1097-2765(01)00408-7. PMID 11779494.
• Kuschel B, Auranen A, McBride S, Novik KL, Antoniou A, Lipscombe JM, Day NE, Easton DF, Ponder BA, Pharoah PD, Dunning A (Jun 2002). "Variants in DNA double-strand break repair genes and breast cancer susceptibility". Human Molecular Genetics 11 (12): 1399–407. doi:10.1093/hmg/11.12.1399. PMID 12023982.
• Mahajan KN, Nick McElhinny SA, Mitchell BS, Ramsden DA (Jul 2002). "Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair". Molecular and Cellular Biology 22 (14): 5194–202. doi:10.1128/MCB.22.14.5194-5202.2002. PMC 139779. PMID 12077346.
• Roth DB (Jul 2002). "Amplifying mechanisms of lymphomagenesis". Molecular Cell 10 (1): 1–2. doi:10.1016/S1097-2765(02)00573-7. PMID 12150897.
• Smogorzewska A, Karlseder J, Holtgreve-Grez H, Jauch A, de Lange T (Oct 2002). "DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2". Current Biology 12 (19): 1635–44. doi:10.1016/S0960-9822(02)01179-X. PMID 12361565.
• Roddam PL, Rollinson S, O'Driscoll M, Jeggo PA, Jack A, Morgan GJ (Dec 2002). "Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination". Journal of Medical Genetics 39 (12): 900–5. doi:10.1136/jmg.39.12.900. PMC 1757220. PMID 12471202.