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. 2000 Jul;6(7):928–936. doi: 10.1017/s1355838200000182

Diverse splicing mechanisms fuse the evolutionarily conserved bicistronic MOCS1A and MOCS1B open reading frames.

T A Gray 1, R D Nicholls 1
PMCID: PMC1369970  PMID: 10917590

Abstract

Molybdenum is an essential cofactor in many enzymes, but must first be complexed by molybdopterin, whose synthesis requires four enzymatic activities. The first two enzymes of this pathway are encoded by the MOCS1 locus in humans. We describe here a remarkably well-conserved novel mRNA splicing phenomenon that produces both an apparently bicistronic MOCS1AM-OCS1B transcript, as well as a distinct class of monocistronic transcript. The latter are created by a variety of splicing mechanisms (alternative splice donors, alternative splice acceptors, and exon-skipping) to bypass the normal termination nonsense codon of MOCS1A resulting in fusion of the MOCS1A and MOCS1B open reading frames. Therefore, these "no-nonsense" transcripts encode a single bifunctional protein embodying both MOCS1A and MOCS1B activities. This coexpression profile was observed in vertebrates (human, mouse, cow, rabbit, opossum, and chicken) and invertebrates (fruit fly and nematode) spanning at least 700 million years of evolution. Our phylogenetic data also provide evidence that the bicistronic form of MOCS1 mRNA is likely to only produce MOCS1A protein and, combined with Northern analyses, suggests that MOCS1B is translated only as a fusion with MOCS1A. Taken together, the data presented here demonstrate a very highly conserved and physiologically relevant dynamic splicing scheme that profoundly influences the protein-coding potential of the MOCS1 locus.

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Selected References

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  1. Blumenthal T. Gene clusters and polycistronic transcription in eukaryotes. Bioessays. 1998 Jun;20(6):480–487. doi: 10.1002/(SICI)1521-1878(199806)20:6<480::AID-BIES6>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  2. Blumenthal T. Trans-splicing and polycistronic transcription in Caenorhabditis elegans. Trends Genet. 1995 Apr;11(4):132–136. doi: 10.1016/s0168-9525(00)89026-5. [DOI] [PubMed] [Google Scholar]
  3. Enright A. J., Iliopoulos I., Kyrpides N. C., Ouzounis C. A. Protein interaction maps for complete genomes based on gene fusion events. Nature. 1999 Nov 4;402(6757):86–90. doi: 10.1038/47056. [DOI] [PubMed] [Google Scholar]
  4. Gray T. A., Saitoh S., Nicholls R. D. An imprinted, mammalian bicistronic transcript encodes two independent proteins. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5616–5621. doi: 10.1073/pnas.96.10.5616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Grundner-Culemann E., Martin G. W., 3rd, Harney J. W., Berry M. J. Two distinct SECIS structures capable of directing selenocysteine incorporation in eukaryotes. RNA. 1999 May;5(5):625–635. doi: 10.1017/s1355838299981542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Haas A. L., Siepmann T. J. Pathways of ubiquitin conjugation. FASEB J. 1997 Dec;11(14):1257–1268. doi: 10.1096/fasebj.11.14.9409544. [DOI] [PubMed] [Google Scholar]
  7. Hayward B. E., Moran V., Strain L., Bonthron D. T. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15475–15480. doi: 10.1073/pnas.95.26.15475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hochstrasser M. Ubiquitin-dependent protein degradation. Annu Rev Genet. 1996;30:405–439. doi: 10.1146/annurev.genet.30.1.405. [DOI] [PubMed] [Google Scholar]
  9. Hoff T., Schnorr K. M., Meyer C., Caboche M. Isolation of two Arabidopsis cDNAs involved in early steps of molybdenum cofactor biosynthesis by functional complementation of Escherichia coli mutants. J Biol Chem. 1995 Mar 17;270(11):6100–6107. doi: 10.1074/jbc.270.11.6100. [DOI] [PubMed] [Google Scholar]
  10. Ischia R., Lovisetti-Scamihorn P., Hogue-Angeletti R., Wolkersdorfer M., Winkler H., Fischer-Colbrie R. Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem. 1997 Apr 25;272(17):11657–11662. doi: 10.1074/jbc.272.17.11657. [DOI] [PubMed] [Google Scholar]
  11. Kozak M. Initiation of translation in prokaryotes and eukaryotes. Gene. 1999 Jul 8;234(2):187–208. doi: 10.1016/s0378-1119(99)00210-3. [DOI] [PubMed] [Google Scholar]
  12. Low S. C., Berry M. J. Knowing when not to stop: selenocysteine incorporation in eukaryotes. Trends Biochem Sci. 1996 Jun;21(6):203–208. [PubMed] [Google Scholar]
  13. Marcotte E. M., Pellegrini M., Ng H. L., Rice D. W., Yeates T. O., Eisenberg D. Detecting protein function and protein-protein interactions from genome sequences. Science. 1999 Jul 30;285(5428):751–753. doi: 10.1126/science.285.5428.751. [DOI] [PubMed] [Google Scholar]
  14. Marcotte E. M., Pellegrini M., Thompson M. J., Yeates T. O., Eisenberg D. A combined algorithm for genome-wide prediction of protein function. Nature. 1999 Nov 4;402(6757):83–86. doi: 10.1038/47048. [DOI] [PubMed] [Google Scholar]
  15. Peters J., Wroe S. F., Wells C. A., Miller H. J., Bodle D., Beechey C. V., Williamson C. M., Kelsey G. A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3830–3835. doi: 10.1073/pnas.96.7.3830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Reiss J., Christensen E., Dorche C. Molybdenum cofactor deficiency: first prenatal genetic analysis. Prenat Diagn. 1999 Apr;19(4):386–388. doi: 10.1002/(sici)1097-0223(199904)19:4<386::aid-pd550>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  17. Reiss J., Christensen E., Kurlemann G., Zabot M. T., Dorche C. Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum Genet. 1998 Dec;103(6):639–644. doi: 10.1007/s004390050884. [DOI] [PubMed] [Google Scholar]
  18. Reiss J., Cohen N., Dorche C., Mandel H., Mendel R. R., Stallmeyer B., Zabot M. T., Dierks T. Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency. Nat Genet. 1998 Sep;20(1):51–53. doi: 10.1038/1706. [DOI] [PubMed] [Google Scholar]
  19. Reiss J., Dorche C., Stallmeyer B., Mendel R. R., Cohen N., Zabot M. T. Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Am J Hum Genet. 1999 Mar;64(3):706–711. doi: 10.1086/302296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sloan J., Kinghorn J. R., Unkles S. E. The two subunits of human molybdopterin synthase: evidence for a bicistronic messenger RNA with overlapping reading frames. Nucleic Acids Res. 1999 Feb 1;27(3):854–858. doi: 10.1093/nar/27.3.854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Stallmeyer B., Drugeon G., Reiss J., Haenni A. L., Mendel R. R. Human molybdopterin synthase gene: identification of a bicistronic transcript with overlapping reading frames. Am J Hum Genet. 1999 Mar;64(3):698–705. doi: 10.1086/302295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Stallmeyer B., Schwarz G., Schulze J., Nerlich A., Reiss J., Kirsch J., Mendel R. R. The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1333–1338. doi: 10.1073/pnas.96.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Unkles S. E., Smith J., Kanan G. J., Millar L. J., Heck I. S., Boxer D. H., Kinghorn J. R. The Aspergillus nidulans cnxABC locus is a single gene encoding two catalytic domains required for synthesis of precursor Z, an intermediate in molybdenum cofactor biosynthesis. J Biol Chem. 1997 Nov 7;272(45):28381–28390. doi: 10.1074/jbc.272.45.28381. [DOI] [PubMed] [Google Scholar]

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