LIG4
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. Defects in this gene are the cause of LIG4 syndrome. The yeast homolog of Lig4 is Dnl4.
Interactions
LIG4 has been shown to interact with XRCC4 via its BRCT domain.[2][3] This interaction stabilizes LIG4 protein in cells; cells that are deficient for XRCC4, such as XR-1 cells, have reduced levels of LIG4.[4]
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.[5]
References
- ↑ "Entrez Gene: LIG4 ligase IV, DNA, ATP-dependent".
- ↑ Deshpande RA, Wilson TE (October 2007). "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair (Amst.) 6 (10): 1507–16. doi:10.1016/j.dnarep.2007.04.014. PMC 2064958. PMID 17567543.
- ↑ Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (December 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nat. Struct. Biol. 8 (12): 1015–9. doi:10.1038/nsb725. PMID 11702069.
- ↑ Bryans M, Valenzano MC, Stamato TD (January 1999). "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4". Mutat. Res. 433 (1): 53–8. doi:10.1016/s0921-8777(98)00063-9. PMID 10047779.
- ↑ Mahaney BL, Hammel M, Meek K, Tainer JA, Lees-Miller SP (February 2013). "XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair". Biochem. Cell Biol. 91 (1): 31–41. doi:10.1139/bcb-2012-0058. PMID 23442139.
Further reading
- Wei YF, Robins P, Carter K et al. (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". Mol. Cell. Biol. 15 (6): 3206–16. PMC 230553. PMID 7760816.
- Robins P, Lindahl T (1996). "DNA ligase IV from HeLa cell nuclei". J. Biol. Chem. 271 (39): 24257–61. doi:10.1074/jbc.271.39.24257. PMID 8798671.
- Grawunder U, Wilm M, Wu X et al. (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 (1997). "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV". Curr. Biol. 7 (8): 588–98. doi:10.1016/S0960-9822(06)00258-2. PMID 9259561.
- Grawunder U, Zimmer D, Leiber MR (1998). "DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains". Curr. Biol. 8 (15): 873–6. doi:10.1016/S0960-9822(07)00349-1. PMID 9705934.
- Grawunder U, Zimmer D, Fugmann S et al. (1998). "DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes". Mol. Cell 2 (4): 477–84. doi:10.1016/S1097-2765(00)80147-1. PMID 9809069.
- Riballo E, Critchlow SE, Teo SH et al. (1999). "Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient". Curr. Biol. 9 (13): 699–702. doi:10.1016/S0960-9822(99)80311-X. PMID 10395545.
- Kim ST, Lim DS, Canman CE, Kastan MB (2000). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
- Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA (2000). "Ku Recruits the XRCC4-Ligase IV Complex to DNA Ends". Mol. Cell. Biol. 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 (2000). "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase". J. Biol. Chem. 275 (34): 26196–205. doi:10.1074/jbc.M000491200. PMID 10854421.
- Lee KJ, Huang J, Takeda Y, Dynan WS (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". J. Biol. Chem. 275 (44): 34787–96. doi:10.1074/jbc.M004011200. PMID 10945980.
- Riballo E, Doherty AJ, Dai Y et al. (2001). "Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity". J. Biol. Chem. 276 (33): 31124–32. doi:10.1074/jbc.M103866200. PMID 11349135.
- Sibanda BL, Critchlow SE, Begun J et al. (2002). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nat. Struct. Biol. 8 (12): 1015–9. doi:10.1038/nsb725. PMID 11702069.
- O'Driscoll M, Cerosaletti KM, Girard PM et al. (2002). "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency". Mol. Cell 8 (6): 1175–85. doi:10.1016/S1097-2765(01)00408-7. PMID 11779494.
- Kuschel B, Auranen A, McBride S et al. (2002). "Variants in DNA double-strand break repair genes and breast cancer susceptibility". Hum. Mol. Genet. 11 (12): 1399–407. doi:10.1093/hmg/11.12.1399. PMID 12023982.
- Mahajan KN, Nick McElhinny SA, Mitchell BS, Ramsden DA (2002). "Association of DNA Polymerase μ (pol μ) with Ku and Ligase IV: Role for pol μ in End-Joining Double-Strand Break Repair". Mol. Cell. Biol. 22 (14): 5194–202. doi:10.1128/MCB.22.14.5194-5202.2002. PMC 139779. PMID 12077346.
- Roth DB (2002). "Amplifying mechanisms of lymphomagenesis". Mol. Cell 10 (1): 1–2. doi:10.1016/S1097-2765(02)00573-7. PMID 12150897.
- Smogorzewska A, Karlseder J, Holtgreve-Grez H et al. (2003). "DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2". Curr. Biol. 12 (19): 1635–44. doi:10.1016/S0960-9822(02)01179-X. PMID 12361565.
- Roddam PL, Rollinson S, O'Driscoll M et al. (2003). "Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination". J. Med. Genet. 39 (12): 900–5. doi:10.1136/jmg.39.12.900. PMC 1757220. PMID 12471202.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
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