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Biology:LIG3

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


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

DNA ligase 3 is an enzyme that, in humans, is encoded by the LIG3 gene.[1][2] The human LIG3 gene encodes ATP-dependent DNA ligases that seal interruptions in the phosphodiester backbone of duplex DNA.

There are three families of ATP-dependent DNA ligases in eukaryotes.[3] These enzymes utilize the same three step reaction mechanism; (i) formation of a covalent enzyme-adenylate intermediate; (ii) transfer of the adenylate group to the 5' phosphate terminus of a DNA nick; (iii) phosphodiester bond formation. Unlike LIG1 and LIG4 family members that are found in almost all eukaryotes, LIG3 family members are less widely distributed.[4] The LIG3 gene encodes several distinct DNA ligase species by alternative translation initiation and alternative splicing mechanisms that are described below.

Structure, DNA binding and catalytic activities

Eukaryotic ATP-dependent DNA ligases have related catalytic region that contains three domains, a DNA binding domain, an adenylation domain and an oligonucleotide / oligosaccharide binding-fold domain. When these enzymes engage a nick in duplex DNA, these domains encircle the DNA duplex with each one making contact with the DNA. The structure of the catalytic region of DNA ligase III complexed with a nicked DNA has been determined by X-ray crystallography and is remarkably similar to that formed by the catalytic region of human DNA ligase I bound to nicked DNA.[5] A unique feature of the DNA ligases encoded by the LIG3 gene is an N-terminal zinc finger that resembles the two zinc fingers at the N-terminus of poly (ADP-ribose) polymerase 1 (PARP1).[6] As with the PARP1 zinc fingers, the DNA ligase III zinc finger is involved in binding to DNA strand breaks.[6][7][8] Within the DNA ligase III polypeptide, the zinc finger co-operates with the DNA binding domain to form a DNA binding module.[9] In addition, the adenylation domain and an oligonucleotide/oligosaccharide binding-fold domain form a second DNA binding module.[9] In the jackknife model proposed by the Ellenberger laboratory,[9] the zinc finger-DNA binding domain module serves as a strand break sensor that binds to DNA single strand interruptions irrespective of the nature of the strand break termini. If these breaks are ligatable, they are transferred to the adenylation domain-oligonucleotide/oligosaccharide binding-fold domain module that binds specifically to ligatable nicks. Compared with DNA ligases I and IV, DNA ligase III is the most active enzyme in the intermolecular joining of DNA duplexes.[10] This activity is predominantly dependent upon the DNA ligase III zinc finger suggesting that the two DNA binding modules of DNA ligase III may be able to simultaneously engage duplex DNA ends.[5][9]

Alternative splicing

The alternative translation initiation and splicing mechanisms alter the amino- and carboxy-terminal sequences that flank the DNA ligase III catalytic region.[11][12] In the alternative splicing mechanism, the exon encoding a C-terminal breast cancer susceptibility protein 1 C-terminal (BRCT) domain at the C-terminus of DNA ligase III-alpha is replaced by a short positively charged sequence that acts as a nuclear localization signal, generating DNA ligase III-beta. This alternatively spliced variant has, to date, only been detected in male germs cells.[12] Based on its expression pattern during spermatogenesis, it appears likely that DNA ligase IIIbeta is involved in meiotic recombination and/or DNA repair in haploid sperm but this has not been definitively demonstrated. Although an internal ATG is the preferred site for translation initiation within the DNA ligase III open reading frame, translation initiations does also occur at the first ATG within the open reading frame, resulting in the synthesis of a polypeptide with an N-terminal mitochondrial targeting sequence.[11][13][14]

Cellular function

As mentioned above, DNA ligase III-alpha mRNA encodes nuclear and mitochondrial versions of DNA ligase III-alpha. Nuclear DNA ligase III-alpha exists and functions in a stable complex with the DNA repair protein XRCC1.[15][16] These proteins interact via their C-terminal BRCT domains.[12][17] XRCC1 has no enzymatic activity but instead appears to acts as a scaffold protein by interacting with a large number of proteins involved in base excision and single-strand break repair. The participation of XRCC1 in these pathways is consistent with the phenotype of xrcc1 cells.[15] In contrast to nuclear DNA ligase III-alpha, mitochondrial DNA ligase III-alpha functions independently of XRCC1, which is not found in mitochondria.[18] It appears that nuclear DNA ligase III-alpha forms a complex with XRCC1 in the cytoplasm and the subsequent nuclear targeting of the resultant complex is directed by the XRCC1 nuclear localization signal.[19] While mitochondrial DNA ligase III-alpha also interacts with XRCC1, it is likely that the activity of the mitochondrial targeting sequence of DNA ligase III-alpha is greater than the activity of the XRCC1 nuclear localization signal and that the DNA ligase III-alpha/XRCC1 complex is disrupted when mitochondrial DNA ligase III-alpha passes through the mitochondrial membrane.

Since the LIG3 gene encodes the only DNA ligase in mitochondria, inactivation of the LIG3 gene results in loss of mitochondrial DNA that in turn leads to loss of mitochondrial function.[20][21][22] Fibroblasts with inactivated Lig3 gene can be propagated in the media supplemented with uridine and pyruvate. However, these cells lack mtDNA.[23] Physiological levels of mitochondrial DNA ligase III appear excessive, and cells with 100-fold reduced mitochondrial content of mitochondrial DNA ligase III-alpha maintain normal mtDNA copy number.[23] The essential role of DNA ligase III-alpha in mitochondrial DNA metabolism can be fulfilled by other DNA ligases, including the NAD-dependent DNA ligase of E. coli, if they are targeted to mitochondria.[20][22] Thus, viable cells that lack nuclear DNA ligase III-alpha can be generated. While DNA ligase I is the predominant enzyme that joins Okazaki fragments during DNA replication, it is now evident that the DNA ligase III-alpha/XRCC1 complex enables cells that either lack or have reduced DNA ligase I activity to complete DNA replication.[20][22][24][25] Given the biochemical and cell biology studies linking the DNA ligase III-alpha/XRCC1 complex with excision repair and the repair of DNA single strand breaks,[26][27][28][29] it was surprising that the cells lacking nuclear DNA ligase III-alpha did not exhibit significantly increased sensitivity to DNA damaging agent.[20][22] These studies suggest that there is significant functional redundancy between DNA ligase I and DNA ligase III-alpha in these nuclear DNA repair pathways. In mammalian cells, most DNA double strand breaks are repaired by DNA ligase IV-dependent non-homologous end joining (NHEJ).[30] DNA ligase III-alpha participates in a minor alternative NHEJ pathway that generates chromosomal translocations.[31][32] Unlike the other nuclear DNA repair functions, it appears that the role of DNA ligase III-alpha in alternative NHEJ is independent of XRCC1.[33]

Clinical significance

Unlike the LIG1 and LIG4 genes,[34][35][36][37] inherited mutations in the LIG3 gene have not been identified in the human population. DNA ligase III-alpha has, however, been indirectly implicated in cancer and neurodegenerative diseases. In cancer, DNA ligase III-alpha is frequently overexpressed and this serves as a biomarker to identify cells that are more dependent upon the alternative NHEJ pathway for the repair of DNA double strand breaks.[38][39][40][41] Although the increased activity of the alternative NHEJ pathway causes genomic instability that drives disease progression, it also constitutes a novel target for the development of cancer cell-specific therapeutic strategies.[39][40] Several genes encoding proteins that interact directly with DNA ligase III-alpha or indirectly via interactions with XRCC1 have been identified as being mutated in inherited neurodegenerative diseases.[42][43][44][45][46] Thus, it appears that DNA transactions involving DNA ligase III-alpha play an important role in maintaining the viability of neuronal cells.

LIG3 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.[47] LIG3 is upregulated in chronic myeloid leukemia,[41] multiple myeloma,[48] and breast cancer.[39]

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[citation needed] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[citation needed] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, LIG3 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Notes


References

  1. ↑ "Entrez Gene: Ligase III, DNA, ATP-dependent". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=3980. 
  2. ↑ "Structure and function of the DNA ligases encoded by the mammalian LIG3 gene". Gene 531 (2): 150–7. December 2013. doi:10.1016/j.gene.2013.08.061. PMID 24013086. 
  3. ↑ "Eukaryotic DNA ligases: structural and functional insights". Annu. Rev. Biochem. 77: 313–38. 2008. doi:10.1146/annurev.biochem.77.061306.123941. PMID 18518823. 
  4. ↑ "DNA ligase III: a spotty presence in eukaryotes, but an essential function where tested". Cell Cycle 10 (21): 3636–44. November 2011. doi:10.4161/cc.10.21.18094. PMID 22041657. 
  5. ↑ 5.0 5.1 "Human DNA ligase III recognizes DNA ends by dynamic switching between two DNA-bound states". Biochemistry 49 (29): 6165–76. July 2010. doi:10.1021/bi100503w. PMID 20518483. 
  6. ↑ 6.0 6.1 "DNA ligase III is recruited to DNA strand breaks by a zinc finger motif homologous to that of poly(ADP-ribose) polymerase. Identification of two functionally distinct DNA binding regions within DNA ligase III". Journal of Biological Chemistry 274 (31): 21679–87. July 1999. doi:10.1074/jbc.274.31.21679. PMID 10419478. 
  7. ↑ "Physical and functional interaction between DNA ligase IIIalpha and poly(ADP-Ribose) polymerase 1 in DNA single-strand break repair". Molecular and Cellular Biology 23 (16): 5919–27. August 2003. doi:10.1128/MCB.23.16.5919-5927.2003. PMID 12897160. 
  8. ↑ "The DNA ligase III zinc finger stimulates binding to DNA secondary structure and promotes end joining". Nucleic Acids Res. 28 (18): 3558–63. September 2000. doi:10.1093/nar/28.18.3558. PMID 10982876. 
  9. ↑ 9.0 9.1 9.2 9.3 "Two DNA-binding and nick recognition modules in human DNA ligase III". Journal of Biological Chemistry 283 (16): 10764–72. April 2008. doi:10.1074/jbc.M708175200. PMID 18238776. 
  10. ↑ "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase". Journal of Biological Chemistry 275 (34): 26196–205. August 2000. doi:10.1074/jbc.M000491200. PMID 10854421. 
  11. ↑ 11.0 11.1 "The human DNA ligase III gene encodes nuclear and mitochondrial proteins". Molecular and Cellular Biology 19 (5): 3869–76. May 1999. doi:10.1128/MCB.19.5.3869. PMID 10207110. 
  12. ↑ 12.0 12.1 12.2 "An alternative splicing event which occurs in mouse pachytene spermatocytes generates a form of DNA ligase III with distinct biochemical properties that may function in meiotic recombination". Molecular and Cellular Biology 17 (2): 989–98. February 1997. doi:10.1128/MCB.17.2.989. PMID 9001252. 
  13. ↑ "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. 
  14. ↑ "Mammalian DNA ligase III: molecular cloning, chromosomal localization, and expression in spermatocytes undergoing meiotic recombination". Molecular and Cellular Biology 15 (10): 5412–22. October 1995. doi:10.1128/MCB.15.10.5412. PMID 7565692. 
  15. ↑ 15.0 15.1 "An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III". Molecular and Cellular Biology 14 (1): 68–76. January 1994. doi:10.1128/MCB.14.1.68. PMID 8264637. 
  16. ↑ "Characterization of the XRCC1-DNA ligase III complex in vitro and its absence from mutant hamster cells". Nucleic Acids Res. 23 (23): 4836–43. December 1995. doi:10.1093/nar/23.23.4836. PMID 8532526. 
  17. ↑ "XRCC1 protein interacts with one of two distinct forms of DNA ligase III". Biochemistry 36 (17): 5207–11. April 1997. doi:10.1021/bi962281m. PMID 9136882. 
  18. ↑ "Mitochondrial DNA ligase III function is independent of Xrcc1". Nucleic Acids Res. 28 (20): 3880–6. October 2000. doi:10.1093/nar/28.20.3880. PMID 11024166. 
  19. ↑ "XRCC1 phosphorylation by CK2 is required for its stability and efficient DNA repair". DNA Repair (Amst.) 9 (7): 835–41. July 2010. doi:10.1016/j.dnarep.2010.04.008. PMID 20471329. 
  20. ↑ 20.0 20.1 20.2 20.3 "DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair". Nature 471 (7337): 240–4. March 2011. doi:10.1038/nature09773. PMID 21390131. Bibcode: 2011Natur.471..240G. 
  21. ↑ "Antisense-mediated decrease in DNA ligase III expression results in reduced mitochondrial DNA integrity". Nucleic Acids Res. 29 (3): 668–76. February 2001. doi:10.1093/nar/29.3.668. PMID 11160888. 
  22. ↑ 22.0 22.1 22.2 22.3 "Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair". Nature 471 (7337): 245–8. March 2011. doi:10.1038/nature09794. PMID 21390132. Bibcode: 2011Natur.471..245S. 
  23. ↑ 23.0 23.1 Shokolenko, IN; Fayzulin, RZ; Katyal, S; McKinnon, PJ; Alexeyev, MF (Sep 13, 2013). "Mitochondrial DNA ligase is dispensable for the viability of cultured cells but essential for mtDNA maintenance". Journal of Biological Chemistry 288 (37): 26594–605. doi:10.1074/jbc.M113.472977. PMID 23884459. 
  24. ↑ "Functional redundancy between DNA ligases I and III in DNA replication in vertebrate cells". Nucleic Acids Research 40 (6): 2599–610. March 2012. doi:10.1093/nar/gkr1024. PMID 22127868. 
  25. ↑ "Partial complementation of a DNA ligase I deficiency by DNA ligase III and its impact on cell survival and telomere stability in mammalian cells". Cellular and Molecular Life Sciences 69 (17): 2933–49. September 2012. doi:10.1007/s00018-012-0975-8. PMID 22460582. 
  26. ↑ "Involvement of XRCC1 and DNA ligase III gene products in DNA base excision repair". Journal of Biological Chemistry 272 (38): 23970–5. September 1997. doi:10.1074/jbc.272.38.23970. PMID 9295348. 
  27. ↑ "Translocation of XRCC1 and DNA ligase III-alpha from centrosomes to chromosomes in response to DNA damage in mitotic human cells". Nucleic Acids Res. 33 (1): 422–9. 2005. doi:10.1093/nar/gki190. PMID 15653642. 
  28. ↑ "Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein". EMBO Journal 15 (23): 6662–70. December 1996. doi:10.1002/j.1460-2075.1996.tb01056.x. PMID 8978692. 
  29. ↑ "Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III alpha in a cell-cycle-specific manner". Molecular Cell 27 (2): 311–23. July 2007. doi:10.1016/j.molcel.2007.06.014. PMID 17643379. http://sro.sussex.ac.uk/id/eprint/30578/1/1-s2.0-S1097276507004042-main.pdf. 
  30. ↑ Lieber MR (2010). "The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway". Annu. Rev. Biochem. 79: 181–211. doi:10.1146/annurev.biochem.052308.093131. PMID 20192759. 
  31. ↑ "DNA ligase III as a candidate component of backup pathways of nonhomologous end joining". Cancer Res. 65 (10): 4020–30. May 2005. doi:10.1158/0008-5472.CAN-04-3055. PMID 15899791. 
  32. ↑ Haber, James E, ed (June 2011). "DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation". PLOS Genet. 7 (6): e1002080. doi:10.1371/journal.pgen.1002080. PMID 21655080. 
  33. ↑ "Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1)". Proceedings of the National Academy of Sciences, USA 109 (7): 2473–8. February 2012. doi:10.1073/pnas.1121470109. PMID 22308491. Bibcode: 2012PNAS..109.2473B. 
  34. ↑ "Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms". Human Molecular Genetics 13 (20): 2369–76. October 2004. doi:10.1093/hmg/ddh274. PMID 15333585. 
  35. ↑ "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. 
  36. ↑ "Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient". Curr. Biol. 9 (13): 699–702. July 1999. doi:10.1016/S0960-9822(99)80311-X. PMID 10395545. 
  37. ↑ "Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents". Cell 69 (3): 495–503. May 1992. doi:10.1016/0092-8674(92)90450-Q. PMID 1581963. 
  38. ↑ "Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair". Cancer Res. 68 (9): 3169–77. May 2008. doi:10.1158/0008-5472.CAN-07-6636. PMID 18451142. 
  39. ↑ 39.0 39.1 39.2 "Targeting abnormal DNA repair in therapy-resistant breast cancers". Molecular Cancer Research 10 (1): 96–107. 2012. doi:10.1158/1541-7786.MCR-11-0255. PMID 22112941. 
  40. ↑ 40.0 40.1 "Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias". Oncogene 32 (14): 1784–93. April 2013. doi:10.1038/onc.2012.203. PMID 22641215. 
  41. ↑ 41.0 41.1 "Up-regulation of WRN and DNA ligase III-alpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks". Blood 112 (4): 1413–23. August 2008. doi:10.1182/blood-2007-07-104257. PMID 18524993. 
  42. ↑ "The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates". Nature 443 (7112): 713–6. October 2006. doi:10.1038/nature05164. PMID 16964241. Bibcode: 2006Natur.443..713A. 
  43. ↑ "Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene". Nature Genetics 29 (2): 184–8. October 2001. doi:10.1038/ng1001-184. PMID 11586299. 
  44. ↑ "The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin". Nature Genetics 29 (2): 189–93. October 2001. doi:10.1038/ng1001-189. PMID 11586300. 
  45. ↑ "Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1". Nature 434 (7029): 108–13. March 2005. doi:10.1038/nature03314. PMID 15744309. Bibcode: 2005Natur.434..108E. 
  46. ↑ "Mutations in PNKP cause microcephaly, seizures and defects in DNA repair". Nature Genetics 42 (3): 245–9. March 2010. doi:10.1038/ng.526. PMID 20118933. 
  47. ↑ "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6 (3): e1697. 2015. doi:10.1038/cddis.2015.58. PMID 25789972. 
  48. ↑ "Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability". PLOS ONE 10 (3): e0121581. 2015. doi:10.1371/journal.pone.0121581. PMID 25790254. Bibcode: 2015PLoSO..1021581H. 

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