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Mol Cell Biol. Feb 1997; 17(2): 989–998.
PMCID: PMC231824

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.


Three mammalian genes encoding DNA ligases have been identified. However, the role of each of these enzymes in mammalian DNA metabolism has not been established. In this study, we show that two forms of mammalian DNA ligase III, alpha and beta, are produced by a conserved tissue-specific alternative splicing mechanism involving exons encoding the C termini of the polypeptides. DNA ligase III-alpha cDNA, which encodes a 103-kDa polypeptide, is expressed in all tissues and cells, whereas DNA ligase III-beta cDNA, which encodes a 96-kDa polypeptide, is expressed only in the testis. During male germ cell differentiation, elevated expression of DNA ligase III-beta mRNA is restricted, beginning only in the latter stages of meiotic prophase and ending in the round spermatid stage. In 96-kDa DNA ligase III-beta, the C-terminal 77 amino acids of DNA ligase III-alpha are replaced by a different 17- to 18-amino acid sequence. As reported previously, the 103-kDa DNA ligase III-alpha interacts with the DNA strand break repair protein encoded by the human XRCC1 gene. In contrast, the 96-kDa DNA ligase III-beta does not interact with XRCC1, indicating that DNA ligase III-beta may play a role in cellular functions distinct from the DNA repair pathways involving the DNA ligase III-alpha x XRCC1 complex. The distinct biochemical properties of DNA ligase III-beta, in combination with the tissue- and cell-type-specific expression of DNA ligase III-beta mRNA, suggest that this form of DNA ligase III is specifically involved in the completion of homologous recombination events that occur during meiotic prophase.

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Selected References

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  • Alcivar AA, Hake LE, Hecht NB. DNA polymerase-beta and poly(ADP)ribose polymerase mRNAs are differentially expressed during the development of male germinal cells. Biol Reprod. 1992 Feb;46(2):201–207. [PubMed]
  • Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993 May;7(5):812–821. [PubMed]
  • Bardwell L, Cooper AJ, Friedberg EC. Stable and specific association between the yeast recombination and DNA repair proteins RAD1 and RAD10 in vitro. Mol Cell Biol. 1992 Jul;12(7):3041–3049. [PMC free article] [PubMed]
  • Barnes DE, Johnston LH, Kodama K, Tomkinson AE, Lasko DD, Lindahl T. Human DNA ligase I cDNA: cloning and functional expression in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6679–6683. [PMC free article] [PubMed]
  • Barnes DE, Tomkinson AE, Lehmann AR, Webster AD, Lindahl T. Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell. 1992 May 1;69(3):495–503. [PubMed]
  • Bellvé AR, Cavicchia JC, Millette CF, O'Brien DA, Bhatnagar YM, Dym M. Spermatogenic cells of the prepuberal mouse. Isolation and morphological characterization. J Cell Biol. 1977 Jul;74(1):68–85. [PMC free article] [PubMed]
  • Bishop DK. RecA homologs Dmc1 and Rad51 interact to form multiple nuclear complexes prior to meiotic chromosome synapsis. Cell. 1994 Dec 16;79(6):1081–1092. [PubMed]
  • Caldecott KW, McKeown CK, Tucker JD, Ljungquist S, Thompson LH. An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III. Mol Cell Biol. 1994 Jan;14(1):68–76. [PMC free article] [PubMed]
  • Caldecott KW, Tucker JD, Stanker LH, Thompson LH. Characterization of the XRCC1-DNA ligase III complex in vitro and its absence from mutant hamster cells. Nucleic Acids Res. 1995 Dec 11;23(23):4836–4843. [PMC free article] [PubMed]
  • Chen J, Tomkinson AE, Ramos W, Mackey ZB, Danehower S, Walter CA, Schultz RA, Besterman JM, Husain I. Mammalian DNA ligase III: molecular cloning, chromosomal localization, and expression in spermatocytes undergoing meiotic recombination. Mol Cell Biol. 1995 Oct;15(10):5412–5422. [PMC free article] [PubMed]
  • de Murcia G, Ménissier de Murcia J. Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci. 1994 Apr;19(4):172–176. [PubMed]
  • Fujimoto H, Erickson RP, Toné S. Changes in polyadenylation of lactate dehydrogenase-X mRNA during spermatogenesis in mice. Mol Reprod Dev. 1988;1(1):27–34. [PubMed]
  • Glisin V, Crkvenjakov R, Byus C. Ribonucleic acid isolated by cesium chloride centrifugation. Biochemistry. 1974 Jun 4;13(12):2633–2637. [PubMed]
  • Goodson ML, Park-Sarge OK, Sarge KD. Tissue-dependent expression of heat shock factor 2 isoforms with distinct transcriptional activities. Mol Cell Biol. 1995 Oct;15(10):5288–5293. [PMC free article] [PubMed]
  • Gu W, Morales C, Hecht NB. In male mouse germ cells, copper-zinc superoxide dismutase utilizes alternative promoters that produce multiple transcripts with different translation potential. J Biol Chem. 1995 Jan 6;270(1):236–243. [PubMed]
  • Haaf T, Golub EI, Reddy G, Radding CM, Ward DC. Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2298–2302. [PMC free article] [PubMed]
  • Hake LE, Alcivar AA, Hecht NB. Changes in mRNA length accompany translational regulation of the somatic and testis-specific cytochrome c genes during spermatogenesis in the mouse. Development. 1990 Sep;110(1):249–257. [PubMed]
  • Hake LE, Kuemmerle N, Hecht NB, Kozak CA. The genes encoding the somatic and testis-specific isotypes of the mouse cytochrome c genes map to paralogous regions of chromosomes 6 and 2. Genomics. 1994 Apr;20(3):503–505. [PubMed]
  • Henderson LM, Arlett CF, Harcourt SA, Lehmann AR, Broughton BC. Cells from an immunodeficient patient (46BR) with a defect in DNA ligation are hypomutable but hypersensitive to the induction of sister chromatid exchanges. Proc Natl Acad Sci U S A. 1985 Apr;82(7):2044–2048. [PMC free article] [PubMed]
  • Inoue M, Kurihara T, Yamashita M, Tatsumi K. Effects of treatment with methyl methanesulfonate during meiotic and postmeiotic stages and maturation of spermatozoa in mice. Mutat Res. 1993 Aug;294(2):179–186. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Lasko DD, Tomkinson AE, Lindahl T. Mammalian DNA ligases. Biosynthesis and intracellular localization of DNA ligase I. J Biol Chem. 1990 Jul 25;265(21):12618–12622. [PubMed]
  • Lehmann AR, Willis AE, Broughton BC, James MR, Steingrimsdottir H, Harcourt SA, Arlett CF, Lindahl T. Relation between the human fibroblast strain 46BR and cell lines representative of Bloom's syndrome. Cancer Res. 1988 Nov 15;48(22):6343–6347. [PubMed]
  • Ljungquist S, Kenne K, Olsson L, Sandström M. Altered DNA ligase III activity in the CHO EM9 mutant. Mutat Res. 1994 Mar;314(2):177–186. [PubMed]
  • Masson N, Hurst HC, Lee KA. Identification of proteins that interact with CREB during differentiation of F9 embryonal carcinoma cells. Nucleic Acids Res. 1993 Jun 11;21(11):1163–1169. [PMC free article] [PubMed]
  • McCarrey JR, Berg WM, Paragioudakis SJ, Zhang PL, Dilworth DD, Arnold BL, Rossi JJ. Differential transcription of Pgk genes during spermatogenesis in the mouse. Dev Biol. 1992 Nov;154(1):160–168. [PubMed]
  • Nevins JR. The pathway of eukaryotic mRNA formation. Annu Rev Biochem. 1983;52:441–466. [PubMed]
  • Prasad R, Singhal RK, Srivastava DK, Molina JT, Tomkinson AE, Wilson SH. Specific interaction of DNA polymerase beta and DNA ligase I in a multiprotein base excision repair complex from bovine testis. J Biol Chem. 1996 Jul 5;271(27):16000–16007. [PubMed]
  • Prigent C, Satoh MS, Daly G, Barnes DE, Lindahl T. Aberrant DNA repair and DNA replication due to an inherited enzymatic defect in human DNA ligase I. Mol Cell Biol. 1994 Jan;14(1):310–317. [PMC free article] [PubMed]
  • Romrell LJ, Bellvé AR, Fawcett DW. Separation of mouse spermatogenic cells by sedimentation velocity. A morphological characterization. Dev Biol. 1976 Mar;49(1):119–131. [PubMed]
  • Ron D, Dressler H. pGSTag--a versatile bacterial expression plasmid for enzymatic labeling of recombinant proteins. Biotechniques. 1992 Dec;13(6):866–869. [PubMed]
  • Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. [PubMed]
  • Sobol RW, Horton JK, Kühn R, Gu H, Singhal RK, Prasad R, Rajewsky K, Wilson SH. Requirement of mammalian DNA polymerase-beta in base-excision repair. Nature. 1996 Jan 11;379(6561):183–186. [PubMed]
  • Söderhäll S. DNA ligases during rat liver regeneration. Nature. 1976 Apr 15;260(5552):640–642. [PubMed]
  • Speed RM. Meiosis in the foetal mouse ovary. I. An analysis at the light microscope level using surface-spreading. Chromosoma. 1982;85(3):427–437. [PubMed]
  • Teo IA, Arlett CF, Harcourt SA, Priestley A, Broughton BC. Multiple hypersensitivity to mutagens in a cell strain (46BR) derived from a patient with immuno-deficiencies. Mutat Res. 1983 Feb;107(2):371–386. [PubMed]
  • Thompson LH, Brookman KW, Jones NJ, Allen SA, Carrano AV. Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange. Mol Cell Biol. 1990 Dec;10(12):6160–6171. [PMC free article] [PubMed]
  • Tomkinson AE, Lasko DD, Daly G, Lindahl T. Mammalian DNA ligases. Catalytic domain and size of DNA ligase I. J Biol Chem. 1990 Jul 25;265(21):12611–12617. [PubMed]
  • Waga S, Bauer G, Stillman B. Reconstitution of complete SV40 DNA replication with purified replication factors. J Biol Chem. 1994 Apr 8;269(14):10923–10934. [PubMed]
  • Walter CA, Lu J, Bhakta M, Zhou ZQ, Thompson LH, McCarrey JR. Testis and somatic Xrcc-1 DNA repair gene expression. Somat Cell Mol Genet. 1994 Nov;20(6):451–461. [PubMed]
  • Walter CA, Trolian DA, McFarland MB, Street KA, Gurram GR, McCarrey JR. Xrcc-1 expression during male meiosis in the mouse. Biol Reprod. 1996 Sep;55(3):630–635. [PubMed]
  • Wei YF, Robins P, Carter K, Caldecott K, Pappin DJ, Yu GL, Wang RP, Shell BK, Nash RA, Schär P, et al. 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. 1995 Jun;15(6):3206–3216. [PMC free article] [PubMed]
  • Wilcock D, Lane DP. Localization of p53, retinoblastoma and host replication proteins at sites of viral replication in herpes-infected cells. Nature. 1991 Jan 31;349(6308):429–431. [PubMed]

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