LIG4

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene.[1]

## Contents

* 1 Function
* 2 LIG4 Syndrome
* 3 Haematopoietic stem cell aging
* 4 Interactions
* 5 Mechanism
* 6 References
* 7 Further reading

## 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][2] This interaction stabilizes LIG4 protein in cells; cells that are deficient for XRCC4, such as XR-1 cells, have reduced levels of LIG4.[9]

## 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.[10]

## References

1. ↑ "Entrez Gene: LIG4 ligase IV, DNA, ATP-dependent". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3981.
2. ↑ 2.0 2.1 "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. December 2001. doi:10.1038/nsb725. PMID 11702069.
3. ↑ "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. February 2010. doi:10.1073/pnas.0914865107. PMID 20133615. Bibcode: 2010PNAS..107.3024R.
4. ↑ 4.0 4.1 4.2 "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. August 2013. doi:10.1038/cdd.2013.44. PMID 23722522.
5. ↑ "Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age". Nature 447 (7145): 725–9. June 2007. doi:10.1038/nature05862. PMID 17554309. Bibcode: 2007Natur.447..725R.
6. ↑ "Chapter 1: Cancer and aging as consequences of un-repaired DNA damage". New Research on DNA Damages. New York: Nova Science Publishers, Inc.. 2008. pp. 1–47. ISBN 978-1-60456-581-2. https://www.novapublishers.com/catalog/product_info.php?products_id=43247. Retrieved 2015-05-20.
7. ↑ 7.0 7.1 "DNA repair is limiting for haematopoietic stem cells during ageing". Nature 447 (7145): 686–90. June 2007. doi:10.1038/nature05875. PMID 17554302. Bibcode: 2007Natur.447..686N.
8. ↑ "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair 6 (10): 1507–16. October 2007. doi:10.1016/j.dnarep.2007.04.014. PMID 17567543.
9. ↑ "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4". Mutation Research 433 (1): 53–8. January 1999. doi:10.1016/s0921-8777(98)00063-9. PMID 10047779.
10. ↑ "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 91 (1): 31–41. February 2013. doi:10.1139/bcb-2012-0058. PMID 23442139.

## Further reading

* "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. June 1995. doi:10.1128/mcb.15.6.3206. PMID 7760816.
* "DNA ligase IV from HeLa cell nuclei". The Journal of Biological Chemistry 271 (39): 24257–61. September 1996. doi:10.1074/jbc.271.39.24257. PMID 8798671.
* "Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells". Nature 388 (6641): 492–5. July 1997. doi:10.1038/41358. PMID 9242410.
* "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV". Current Biology 7 (8): 588–98. August 1997. doi:10.1016/S0960-9822(06)00258-2. PMID 9259561.
* "DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains". Current Biology 8 (15): 873–6. July 1998. doi:10.1016/S0960-9822(07)00349-1. PMID 9705934.
* "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. October 1998. doi:10.1016/S1097-2765(00)80147-1. PMID 9809069.
* "Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient". Current Biology 9 (13): 699–702. July 1999. doi:10.1016/S0960-9822(99)80311-X. PMID 10395545.
* "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry 274 (53): 37538–43. December 1999. doi:10.1074/jbc.274.53.37538. PMID 10608806.
* "Ku recruits the XRCC4-ligase IV complex to DNA ends". Molecular and Cellular Biology 20 (9): 2996–3003. May 2000. doi:10.1128/MCB.20.9.2996-3003.2000. PMID 10757784.
* "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. August 2000. doi:10.1074/jbc.M000491200. PMID 10854421.
* "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. November 2000. doi:10.1074/jbc.M004011200. PMID 10945980.
* "Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity". The Journal of Biological Chemistry 276 (33): 31124–32. August 2001. doi:10.1074/jbc.M103866200. PMID 11349135.
* "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. December 2001. doi:10.1038/nsb725. PMID 11702069.
* "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency". Molecular Cell 8 (6): 1175–85. December 2001. doi:10.1016/S1097-2765(01)00408-7. PMID 11779494.
* "Variants in DNA double-strand break repair genes and breast cancer susceptibility". Human Molecular Genetics 11 (12): 1399–407. June 2002. doi:10.1093/hmg/11.12.1399. PMID 12023982.
* "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. July 2002. doi:10.1128/MCB.22.14.5194-5202.2002. PMID 12077346.
* "Amplifying mechanisms of lymphomagenesis". Molecular Cell 10 (1): 1–2. July 2002. doi:10.1016/S1097-2765(02)00573-7. PMID 12150897.
* "DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2". Current Biology 12 (19): 1635–44. October 2002. doi:10.1016/S0960-9822(02)01179-X. PMID 12361565. http://delangelab.rockefeller.edu/pubs/69_Smogorzewska_Curr_Biol_2002.pdf.
* "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. December 2002. doi:10.1136/jmg.39.12.900. PMID 12471202.

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PDB gallery

* 1ik9: CRYSTAL STRUCTURE OF A XRCC4-DNA LIGASE IV COMPLEX

* 2e2w: Solution structure of the first BRCT domain of human DNA ligase IV

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