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Journal of Biosciences

, 44:139 | Cite as

Translin: A multifunctional protein involved in nucleic acid metabolism

  • Alka Gupta
  • Vinayaki S Pillai
  • Rajani Kant ChittelaEmail author
Review
  • 25 Downloads

Abstract

Translin, a highly conserved, DNA/RNA binding protein, is abundantly expressed in brain, testis and in certain malignancies. It was discovered initially in the quest to find proteins that bind to alternating polypurines-polypyrimidines repeats. It has been implicated to have a role in RNA metabolism (tRNA processing, RNAi, RNA transport, etc.), transcription, DNA damage response, etc. Studies from human, mice, drosophila and yeast have revealed that it forms an octameric ring, which is important for its function. Translin is a cytoplasmic protein, but under genotoxic stress, it migrates into the nucleus, binds to the break point hot spots and therefore, thought to be involved in chromosomal translocation events as well as DNA damage related response. Its structure is known and DNA binding regions, GTP binding region and regions responsible for homotypic and heterotypic interaction are known. It forms a ball like structure with open central channel for accommodating the substrate nucleic acids. Besides this, translin protein binds to 3′ and 5′ UTR of certain mRNAs and probably regulates their availability for translation. It is also involved in mRNA transport and cell cycle progression. It forms a heteromeric complex with translin associated factor-X (TRAX) to form C3PO complex which is involved in RNA silencing process. Recently, it has been shown that translin is upregulated under starvation conditions in Drosophila and is involved in the integration of sleep and metabolic rate of the flies. Earlier studies classified translin as a DNA repair protein; however subsequent studies showed that it is a multifunctional protein. With this background, in this review we have summarized the translin biochemical activities, cellular function as well as structural properties of this important protein.

Keywords

DNA binding DNA repair RNA binding Translin translocations TRAX 

Notes

Acknowledgements

We sincerely thank Dr. B. J. Rao, IISER, Tirupati, Andhra Pradesh, for constant support and discussions during our work on translin. We acknowledge Dr. H.S. Misra, Head, Molecular Biology Division, BARC, Mumbai, for his valuable suggestions. We also thank Dr. Anand Ballal and all the members of the lab, MDRS, MBD, BARC, for their constant help and discussions. VSP, Ph.D. student, acknowledges Homi Bhabha National Institute (HBNI), BARC, Mumbai, for the fellowship.

References

  1. Aharoni A, Baran N and Manor H 1993 Characterization of a multisubunit human protein which selectively binds single stranded d(GA)n and d(GT)n sequence repeats in DNA. Nucleic Acids Res. 21 5221–5228PubMedPubMedCentralCrossRefGoogle Scholar
  2. Aoki K, Suzuki K, Sugano T, Tasaka T, Nakahara K, Kuge O, Omori A and Kasai M 1995 A novel gene, Translin, encodes a recombination hotspot binding protein associated with chromosomal translocations. Nat. Genet. 10 167–174PubMedCrossRefPubMedCentralGoogle Scholar
  3. Aoki K, Ishida R and Kasai M 1997 Isolation and characterization of a cDNA encoding a Translin-like protein, TRAX. FEBS Lett. 401 109–112PubMedCrossRefPubMedCentralGoogle Scholar
  4. Aoki K, Suzuki K, Ishida R and Kasai M 1999 The DNA binding activity of Translin is mediated by a basic region in the ring-shaped structure conserved in evolution. FEBS Lett. 443 363–366PubMedCrossRefPubMedCentralGoogle Scholar
  5. Asada K, Canestrari E, Fu X, Li Z, Makowski E, Wu YC, Mito JK, Kirsch DG, Baraban J and Paroo Z 2014 Rescuing dicer defects via inhibition of an anti-dicing nuclease. Cell Rep. 9 41471–84141CrossRefGoogle Scholar
  6. Castro A, Peter M, Magnaghi-Jaulin L, Vigneron S, Loyaux D, Lorca T and Labbé JC 2000 Part of Xenopus translin is localized in the centrosomes during mitosis. Biochem. Biophys. Res. Commun. 2000 276 515–523PubMedCrossRefPubMedCentralGoogle Scholar
  7. Chalk JG, Barr FG and Mitchell CD 1997 Translin recognition site sequences flank chromosome translocation breakpoints in alveolar rhabdomyosarcoma cell lines. Oncogene. 15 1199–1205PubMedCrossRefPubMedCentralGoogle Scholar
  8. Chennathukuzhi V, Morales CR, El-alfy M and Hecht NB 2003 The kinesin KIF17b and RNA-binding protein TB-RBP transport specific cAMP-responsive element modulator-regulated mRNAs in male germ cells. Proc. Natl. Acad. Sci. USA. 100 15566–15571PubMedCrossRefPubMedCentralGoogle Scholar
  9. Chennathukuzhi VM, Kurihara Y, Bray JD, Yang J and Hecht NB 2001 Altering the GTP binding site of the DNA/RNA-binding protein, Translin/TB-RBP, decreases RNA binding and may create a dominant negative phenotype. Nucleic Acids Res. 29 4433–4440PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chiaruttini C, Vicario A, Li Z, Baj G, Braiuca P, Wu Y, Lee FS, Gardossi L, Baraban JM and Tongiorgi E 2009 Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. Proc. Natl. Acad. Sci. USA. 106 16481–16486PubMedCrossRefPubMedCentralGoogle Scholar
  11. Chittela RK, Gupta GD and Ballal A 2014 Characterization of a plant (rice) translin and its comparative analysis with human translin. Planta. 240 357–368PubMedCrossRefPubMedCentralGoogle Scholar
  12. Eliahoo E, Ben yosef R, Pérez-cano L, Fernández-recio J, Glaser F and Manor H 2010 Mapping of interaction sites of the Schizosaccharomyces pombe protein Translin with nucleic acids and proteins: a combined molecular genetics and bioinformatics study. Nucleic Acids Res. 38 2975–2989PubMedPubMedCentralCrossRefGoogle Scholar
  13. Eliahoo E, Marx A, Manor H and Alian A 2015 A novel open-barrel structure of octameric translin reveals a potential RNA entryway. J. Mol. Biol. 427 756–762PubMedCrossRefPubMedCentralGoogle Scholar
  14. Fukuda Y, Ishida R, Aoki K, Nakahara K, Takashi T, Mochida K, Suzuki O, Matsuda J and Kasai M 2008 Contribution of Translin to hematopoietic regeneration after sublethal ionizing irradiation. Biol. Pharm. Bull. 31 207–211PubMedCrossRefPubMedCentralGoogle Scholar
  15. Gu W, Wu XQ, Meng XH, Morales C, El-alfy M and Hecht NB 1998 The RNA- and DNA-binding protein TB-RBP is spatially and developmentally regulated during spermatogenesis. Mol. Reprod. Dev. 49 219–228PubMedCrossRefPubMedCentralGoogle Scholar
  16. Gupta A, Nair A, Ballal A and Chittela RK 2017 C-terminal residues of rice translin are essential for octamer formation and nucleic acid binding. Plant. Physiol. Biochem 118 600–608PubMedCrossRefPubMedCentralGoogle Scholar
  17. Gupta GD, Kale A and Kumar V 2012 Molecular evolution of translin superfamily proteins within the genomes of eubacteria, archaea and eukaryotes. J. Mol. Evol. 75 155–167PubMedCrossRefPubMedCentralGoogle Scholar
  18. Gupta GD, Makde RD, Rao BJ and Kumar V 2008 Crystal structures of Drosophila mutant translin and characterization of translin variants reveal the structural plasticity of translin proteins. FEBS J. 275 4235–4249PubMedCrossRefPubMedCentralGoogle Scholar
  19. Han JR, Gu W and Hecht NB 1995 Testis-brain RNA-binding protein, a testicular translational regulatory RNA-binding protein, is present in the brain and binds to the 3′ untranslated regions of transported brain mRNAs. Biol. Reprod. 53 707–717PubMedCrossRefPubMedCentralGoogle Scholar
  20. Hasegawa T and Isobe K 1999 Evidence for the interaction between Translin and GADD34 in mammalian cells. Biochim. Biophys. Acta. 1428 161–168PubMedCrossRefPubMedCentralGoogle Scholar
  21. Hosaka T, Kanoe H, Nakayama T, Murakami H, Yamamoto H, Nakamata T, Tsuboyama T, Oka M, Kasai M, Sasaki MS, Nakamura T and Toguchida J 2000 Translin binds to the sequences adjacent to the breakpoints of the TLS and CHOP genes in liposarcomas with translocation t(12;6). Oncogene. 19 5821–5825PubMedCrossRefPubMedCentralGoogle Scholar
  22. Ikeuchi Y, Imanishi A, Sudo K, Fukunaga T, Yokoi A, Matsubara L, Goto C, Fukuoka T, Kuronuma K, Kono R, Hasegawa N, Asano S, Ito MR and Okado H 2018 Translin modulates mesenchymal cell proliferation and differentiation in mice. Biochem. Biophys. Res. Commun. 504 115–122PubMedCrossRefPubMedCentralGoogle Scholar
  23. Ishida R1, Okado H, Sato H, Shionoiri C, Aoki K and Kasai M 2002 A role for the octameric ring protein, Translin, in mitotic cell division. FEBS Lett. 525 105–110PubMedCrossRefPubMedCentralGoogle Scholar
  24. Jacob E, Pucshansky L, Zeruya E, Baran N and Manor H 2004 The human protein translin specifically binds single-stranded microsatellite repeats, d(GT)n, and G-strand telomeric repeats, d(TTAGGG)n: a study of the binding parameters. J. Mol. Biol. 344 939–950PubMedCrossRefGoogle Scholar
  25. Jaendling A and Mcfarlane RJ 2010 Biological roles of translin and translin-associated factor-X: RNA metabolism comes to the fore. Biochem J. 429 225–234PubMedCrossRefGoogle Scholar
  26. Kasai M, Aoki K, Matsuo Y, Minowada J, Maziarz RT and Strominger JL 1994 Recombination hotspot associated factors specifically recognize novel target sequences at the site of interchromosomal rearrangements in T-ALL patients with t(8;14)(q24;q11) and t(1;14)(p32;q11). Int. Immunol. 6 1017–1025PubMedCrossRefGoogle Scholar
  27. Kasai M, Matsuzaki T, Katayanagi K, Omori A, Maziarz RT, Strominger JL, Aoki K and Suzuki K 1997 The translin ring specifically recognizes DNA ends at recombination hot spots in the human genome. J. Biol. Chem. 272 11402–11407PubMedCrossRefGoogle Scholar
  28. Kumar V and Gupta GD 2012 Low-resolution structure of Drosophila translin. FEBS Open Bio. 2 37–46PubMedPubMedCentralCrossRefGoogle Scholar
  29. Kwon YK and Hecht NB 1993 Binding of a phosphoprotein to the 3′ untranslated region of the mouse protamine 2 mRNA temporally represses its translation. Mol. Cell Biol. 13 6547–6557PubMedPubMedCentralCrossRefGoogle Scholar
  30. Kwon YK and Hecht NB 1991 Cytoplasmic protein binding to highly conserved sequences in the 3′ untranslated region of mouse protamine 2 mRNA, a translationally regulated transcript of male germ cells. Proc. Natl. Acad. Sci. USA. 88 3584–3588PubMedCrossRefPubMedCentralGoogle Scholar
  31. Laufman O, Ben yosef R, Adir N and Manor H 2005 Cloning and characterization of the Schizosaccharomyces pombe homologs of the human protein Translin and the Translin-associated protein TRAX. Nucleic Acids Res. 33 4128–4139PubMedPubMedCentralCrossRefGoogle Scholar
  32. Li L, Gu W, Liang C, Liu Q, Mello CC and Liu Y 2012 The translin-TRAX complex (C3PO) is a ribonuclease in tRNA processing. Nat. Struct. Mol. Biol. 19 824–830PubMedPubMedCentralCrossRefGoogle Scholar
  33. Liu Y, Ye X, Jiang F, Liang C, Chen D, Peng J, Kinch LN, Grishin NV and Liu Q 2009 C3PO, an endoribonuclease that promotes RNAi by facilitating RISC activation. Science 325 750–753PubMedPubMedCentralCrossRefGoogle Scholar
  34. Murakami K, Yurgel ME, Stahl BA, Masek P, Mehta A, Heidker R, Bollinger W, Gingras RM, Kim YJ, Ja WW, Suter B, DiAngelo JR and Keene AC 2016 Translin is required for metabolic regulation of sleep. Curr. Biol. 26 972–980PubMedPubMedCentralCrossRefGoogle Scholar
  35. Parizotto EA, Lowe ED and Parker JS 2013 Structural basis for duplex RNA recognition and cleavageby Archaeoglobusfulgidus C3PO. Nat. Struct. Mol. Biol. 20 380–388CrossRefGoogle Scholar
  36. Park AJ, Havekes R, Fu X, Hansen R, Tudor JC, Peixoto L, Li Z, Wu YC, Poplawski SG, Baraban JM and Abel T 2017 Learning induces the translin/trax RNase complex to express activin receptors for persistent memory. Elife. 6 e27872Google Scholar
  37. Pérez-Cano L, Eliahoo E, Lasker K, Wolfson HJ, Glaser F, Manor H, Bernadó P and Fernández-Recio J 2013 Conformational transitions in human translin enable nucleic acid binding. Nucleic Acids Res. 41 9956–9966PubMedPubMedCentralCrossRefGoogle Scholar
  38. Sengupta K, Kamdar RP, D’souza JS, Mustafi SM and Rao BJ 2006 GTP-induced conformational changes in translin: a comparison between human and Drosophila proteins. Biochemistry 45 861–870PubMedCrossRefPubMedCentralGoogle Scholar
  39. Sengupta K and Rao BJ 2002 Translin binding to DNA: recruitment through DNA ends and consequent conformational transitions. Biochemistry 41 15315–15326PubMedCrossRefPubMedCentralGoogle Scholar
  40. Sugiura I, Sasaki C, Hasegawa T, Kohno T, Sugio S, Moriyama H, Kasai M and Matsuzaki T 2004 Structure of human translin at 2.2 A resolution. Acta Crystallogr. D 60 674–679PubMedCrossRefPubMedCentralGoogle Scholar
  41. Suseendranathan K, Sengupta K, Rikhy R, D’Souza JS, Kokkanti M, Kulkarni MG, Kamdar R, Changede R, Sinha R, Subramanian L, Singh K, Rodrigues V and Rao BJ 2007 Expression pattern of Drosophila translin and behavioral analyses of the mutant. Eur. J. Cell. Biol. 86 173–186PubMedCrossRefPubMedCentralGoogle Scholar
  42. Taira E, Finkenstadt PM and Baraban JM 1998 Identification of translin and trax as components of the GS1 strand-specific DNA binding complex enriched in brain. J. Neurochem. 71 471–477PubMedCrossRefPubMedCentralGoogle Scholar
  43. TianY, Simanshu DK, Ascano M, Diaz-Avalos R, Park AY, Juranek SA, Rice WJ, Yin Q, Robinson CV, Tuschl T and Patel DJ 2011 Multimeric assembly and biochemical characterization ofthe Trax–translin endonuclease complex. Nat. Struct. Mol. Biol. 18 658–665CrossRefGoogle Scholar
  44. VanLoock MS, Yu X, Kasai M, Egelman EH 2001 Electron microscopic studies of the translin octameric ring. J. Struct. Biol. 135 58–66PubMedCrossRefPubMedCentralGoogle Scholar
  45. Wang J, Boja ES, Oubrahim H and Chock PB 2004 Testis brain ribonucleic acid-binding protein/translin possesses both single-stranded and double-stranded ribonuclease activities. Biochemistry 43 13424–13431PubMedCrossRefPubMedCentralGoogle Scholar
  46. Wu XQ, Gu W, Meng X and Hecht NB 1997 The RNA-binding protein, TB-RBP, is the mouse homologue of translin, a recombination protein associated with chromosomal translocations. Proc. Natl. Acad. Sci. USA. 94 5640–5645PubMedCrossRefPubMedCentralGoogle Scholar
  47. Wu XQ, Lefrancois S, Morales CR and Hecht NB 1999 Protein-protein interactions between the testis brain RNA-binding protein and the transitional endoplasmic reticulum ATPase, a cytoskeletal gamma actin and Trax in male germ cells and the brain. Biochemistry 38 11261–11270PubMedCrossRefPubMedCentralGoogle Scholar
  48. Wu YC, Williamson R, Li Z, Vicario A, Xu J, Kasai M, Chern Y, Tongiorgi E and Baraban JM 2011 Dendritic trafficking of brain-derived neurotrophic factor mRNA: regulation by translin-dependent and -independent mechanisms. J. Neurochem. 116 1112–1121PubMedPubMedCentralCrossRefGoogle Scholar
  49. Ye X, Huang N, Liu Y, Paroo Z, Huerta C, Li P, Chen S, Liu Q and Zhang H 2011 Structure of C3PO and mechanism of human RISC activation. Nat. Struct. Mol. Biol. 18 650–657PubMedPubMedCentralCrossRefGoogle Scholar
  50. Zhang J, Liu H, Yao Q, YuX, ChenY, CuiR,Wu B, Zheng L, Zuo J, Huang Z, Ma J and Gan J 2016 Structural basis for single-stranded RNA recognition and cleavage by C3PO. Nucleic Acids Res. 44 9494–9504PubMedPubMedCentralGoogle Scholar

Copyright information

© Indian Academy of Sciences 2019

Authors and Affiliations

  • Alka Gupta
    • 1
  • Vinayaki S Pillai
    • 1
    • 2
  • Rajani Kant Chittela
    • 1
    • 2
    Email author
  1. 1.Molecular Damage and Repair Section, Molecular Biology DivisionBhabha Atomic Research CentreMumbaiIndia
  2. 2.Homi Bhabha National InstituteMumbaiIndia

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