Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!
Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant over-expression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-of-function caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG)•(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions.
Vyšlo v časopise:
Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!. PLoS Genet 7(3): e32767. doi:10.1371/journal.pgen.1002018
Kategorie:
Review
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002018
Souhrn
Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant over-expression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-of-function caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG)•(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions.
Zdroje
1. López CastelAClearyJDPearsonCE 2010 Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol 11 165 170
2. López CastelANakamoriMToméSChitayatDGourdonGThorntonCAPearsonCE 2010 Expanded CTG repeat demarcates a boundary for abnormal CpG methylation in myotonic dystrophy patient tissues. Hum Mol Genet 20 1 15
3. La SpadaARTaylorJP 2010 Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11 247 258
4. PearsonCE 2010 FSHD: a repeat contraction disease finally ready to expand (our understanding of its pathogenesis). PLoS Genet 6 e1001180 doi:10.1371/journal.pgen.1001180
5. LemmersRJvan der VlietPJKloosterRSacconiSCamañoP 2010 A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329 1650 1653
6. SniderLGengLNLemmersRJKybaMWareCB 2010 Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6 e1001181 doi:10.1371/journal.pgen.10011801
7. ShinJCharizanisKSwansonMS 2009 Pathogenic RNAs in microsatellite expansion disease. Neurosci Lett 466 99 102
8. OostraBAWillemsenR 2009 FMR1: a gene with three faces. Biochim Biophys Acta 1790 467 477
9. MerienneKTrottierY 2009 SCA8 CAG/CTG expansions, a tale of two TOXICities: a unique or common case? PLoS Genet 5 e1000593 doi:10.1371/journal.pgen.1000593
10. DaughtersRSTuttleDLGaoWIkedaYMoseleyML 2009 RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet 5 e1000600 doi:10.1371/journal.pgen.1000600
11. MoseleyMLSchutLJBirdTDKoobMDDayJWRanumLP 2000 SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Hum Mol Genet 9 2125 2130
12. BatraRCharizanisKSwansonMS 2010 Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum Mol Genet 19 R1 R77 R82
13. ZuTGibbensBDotyNSGomes-PereiraMHuguetA 2010 Non-ATG initiated translation directed by microsatellite expansions Proc Natl Acad Sci U S A 108 260 265
14. SonenbergNHinnebuschAG 2009 Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136 731 745
15. MessaedCRouleauGA 2009 Molecular mechanisms underlying polyalanine diseases. Neurobiol Dis 34 397 405
16. KarlinSBurgeC 1996 Trinucleotide repeats and long homopeptides in genes and proteins associated with nervous system disease and development. Proc Natl Acad Sci U S A 93 1560 1565
17. StevensDJWalterEDRodríguezADraperDDaviesP 2009 Early onset prion disease from octarepeat expansion correlates with copper binding properties. PLoS Pathog 5 e1000390 doi:10.1371/journal.ppat.1000390
18. FauxNGBottomleySPLeskAMIrvingJAMorrisonJRde la BandaMGWhisstockJC 2005 Functional insights from the distribution and role of homopeptide repeat-containing proteins. Genome Res 15 537 551
19. Schneider-PoetschTJuJEylerDEDangYBhatS 2010 Inhibitation of eukaryotic translation elongation by cycoheximide and lactimidomycin. Nat Chem Bio 6 209 217
20. OleinickNL 1977 Initiation and elongation of protein synthesis in growing cells: differential inhibition by cycloheximide and emetine. Arch Biochem Biophys 182 171 80
21. GasparCJannatipourMDionPLaganièreJSequeirosJ 2000 CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet 9 1957 1966
22. DaviesJERubinszteinDC 2006 Polyalanine and polyserine frameshift products in Huntington's disease. J Med Genet 43 893 896 Erratum in: J Med Genet 44: 160
23. TouriolCBornesSBonnalSAudigierSPratsH 2003 Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons. Biol Cell 95 169 178
24. JanE 2006 Divergent IRES elements in invertebrates. Virus Research 119 16 28
25. SobczakKKrzyzosiakWJ 2005 CAG repeats containing CAA interruptions form branched hairpin structures in spinocerebellar ataxia type 2 transcripts. J Biol Chem 280 3898 3910
26. LudwigALHersheyJWHagermanPJ 2011 Initiation of translation of the FMR1 mRNA occurs predominantly through 5′end-dependent ribosomal scanning. J Mol Biol Jan 12 Epub ahead of print. PMID: 21237174
27. KozakM 1989 Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol Cell Biol 9 5134 5142
28. FengYZhangFLokeyLKChastainJLLakkisL 1995 Translational suppression by trinucleotide repeat expansion at FMR1. Science 268 731 734
29. RacaGSiyanovaEYMcMurrayCTMirkinSM 2000 Expansion of the (CTG)(n) repeat in the 5′-UTR of a reporter gene impedes translation. Nucleic Acids Res 28 3943 3949
30. MoseleyMLZuTIkedaYGaoWMosemillerAK 2006 Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 38 758 769
31. MusovaZMazanecRKrepelovaAEhlerEValesJ 2009 Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet A 149A 1365 1374
32. BraidaCStefanatosRKAdamBMahajanNSmeetsHJ 2010 Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients. Hum Mol Genet 19 1399 1412
33. AndrewSEGoldbergYPTheilmannJZeislerJHaydenMR 1994 A CCG repeat polymorphism adjacent to the CAG repeat in the Huntington disease gene: implications for diagnostic accuracy and predictive testing. Hum Mol Genet 3 65 67
34. IrvineRAYuMCRossRKCoetzeeGA 1995 The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 55 1937 1940
35. ClearyJDToméSLópez CastelAPanigrahiGBFoiryL 2010 Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus. Nat Struct Mol Biol 17 1079 1087
36. ReilmannRRolfLHLangeHW 1995 Decreased plasma alanine and isoleucine in Huntington's disease. Acta Neurol Scand 91 222 224
37. MoxleyRT3rdKingstonWGriggsRC 1985 Abnormal regulation of venous alanine after glucose ingestion in myotonic dystrophy. Clin Sci 68 151 157
38. LiLBYuZTengXBoniniNM 2008 RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453 1107 1111
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 3
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Whole-Exome Re-Sequencing in a Family Quartet Identifies Mutations As the Cause of a Novel Skeletal Dysplasia
- Origin-Dependent Inverted-Repeat Amplification: A Replication-Based Model for Generating Palindromic Amplicons
- FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
- Limited dCTP Availability Accounts for Mitochondrial DNA Depletion in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)