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RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders.

Wojciechowska M, Olejniczak M, Galka-Marciniak P, Jazurek M, Krzyzosiak WJ - Nucleic Acids Res. (2014)

Bottom Line: Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively.The contribution of unusual translation products to pathogenesis needs to be better understood.In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.

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Speculated mechanisms of ribosomal frameshifting at CAG repeats in SCA3 and HD. Translation elongation is a cyclic process of mRNA-dependent peptide bond formation with the use of ribosomes, aminoacyl-tRNAs, energy and specific protein factors. At the start of each cycle, the complex of correct aminoacyl-tRNA and the elongation factor eEF-1AGTP are positioned in the ribosome decoding center (A site). (a) During this step, the ribosome P site binds the initiator Met-tRNA or peptidyl-tRNA. After codon recognition, followed by GTP hydrolysis, the amino acid from aminoacyl-tRNAs is transferred to the C-terminus of the growing polypeptide chain. (b) The reaction leaves an uncharged tRNA in the ribosomal P site and the new peptidyl-tRNA in the A site. Normally, during the next step, the ribosome translocates one codon forward on the mRNA, and deacylated tRNA is released from the exit (E) site of the ribosome. During translation elongation of expanded CAG-containing transcripts, the ribosomal complex may pause on the hairpin structure formed by the elongated CAG repeat tract. Accommodation of aa-tRNA may pull the downstream mRNA into the ribosome, thus creating tension between the hairpin and slippery site. This leads to the dissociation of peptidyl-tRNA and repairs mRNA in the (−1) frame (GCA). (c) The weak interaction between the codon-anticodon GCA:CUG may result in peptidyl-tRNA drop off. (d) After unwinding of the hairpin, elongation proceeds in a new frame. (e) An increased demand for glutaminyl-tRNAGln-CUG may be the additional factor that stimulates changes in the reading frame. * - refolding hairpin.
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Figure 4: Speculated mechanisms of ribosomal frameshifting at CAG repeats in SCA3 and HD. Translation elongation is a cyclic process of mRNA-dependent peptide bond formation with the use of ribosomes, aminoacyl-tRNAs, energy and specific protein factors. At the start of each cycle, the complex of correct aminoacyl-tRNA and the elongation factor eEF-1AGTP are positioned in the ribosome decoding center (A site). (a) During this step, the ribosome P site binds the initiator Met-tRNA or peptidyl-tRNA. After codon recognition, followed by GTP hydrolysis, the amino acid from aminoacyl-tRNAs is transferred to the C-terminus of the growing polypeptide chain. (b) The reaction leaves an uncharged tRNA in the ribosomal P site and the new peptidyl-tRNA in the A site. Normally, during the next step, the ribosome translocates one codon forward on the mRNA, and deacylated tRNA is released from the exit (E) site of the ribosome. During translation elongation of expanded CAG-containing transcripts, the ribosomal complex may pause on the hairpin structure formed by the elongated CAG repeat tract. Accommodation of aa-tRNA may pull the downstream mRNA into the ribosome, thus creating tension between the hairpin and slippery site. This leads to the dissociation of peptidyl-tRNA and repairs mRNA in the (−1) frame (GCA). (c) The weak interaction between the codon-anticodon GCA:CUG may result in peptidyl-tRNA drop off. (d) After unwinding of the hairpin, elongation proceeds in a new frame. (e) An increased demand for glutaminyl-tRNAGln-CUG may be the additional factor that stimulates changes in the reading frame. * - refolding hairpin.

Mentions: It remains to be established whether frameshifting on CAG repeats results from an incomplete 2-base translocation event ((+2) frameshifting) or ribosome slippage by one base in the 5′ direction ((−1) frameshifting). Both these processes generate the same GCA frame encoding alanine; however, different nomenclature used by the authors may be confusing. Because frameshifting has been shown to occur in both SCA3 and HD, the most straightforward explanation is that the CAG repeat sequences of, respectively, ATXN3 and HTT are particularly susceptible to such repositions of reading frames, as experimental evidence demonstrated a higher frequency of frameshifting on longer repeats of both transcripts (26,28–30). However, as the structural requirements of RNA that induce frameshifting are not sufficiently known, it seems plausible that the hairpin structures formed by elongated CAG repeats of ATXN3 and HTT (Figure 3) (98–100) may serve as frameshifting stimulatory sequences, leading to ribosome pausing (Figure 4). Pseudoknots are a common type of stimulatory motif, but hairpin structures are also used by some viruses, e.g. HIV-1 (101,102). During translation elongation on expanded CAG repeat tracts, multiple hairpin structures may fold and unfold by moving the ribosomal complex. In investigating mechanisms of ribosomal frameshifting within repeated sequences, it would be interesting to determine whether the influence of CAA interruptions which are known to alter structure of CAG repeat hairpins (57) affects the frameshifting frequency.


RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders.

Wojciechowska M, Olejniczak M, Galka-Marciniak P, Jazurek M, Krzyzosiak WJ - Nucleic Acids Res. (2014)

Speculated mechanisms of ribosomal frameshifting at CAG repeats in SCA3 and HD. Translation elongation is a cyclic process of mRNA-dependent peptide bond formation with the use of ribosomes, aminoacyl-tRNAs, energy and specific protein factors. At the start of each cycle, the complex of correct aminoacyl-tRNA and the elongation factor eEF-1AGTP are positioned in the ribosome decoding center (A site). (a) During this step, the ribosome P site binds the initiator Met-tRNA or peptidyl-tRNA. After codon recognition, followed by GTP hydrolysis, the amino acid from aminoacyl-tRNAs is transferred to the C-terminus of the growing polypeptide chain. (b) The reaction leaves an uncharged tRNA in the ribosomal P site and the new peptidyl-tRNA in the A site. Normally, during the next step, the ribosome translocates one codon forward on the mRNA, and deacylated tRNA is released from the exit (E) site of the ribosome. During translation elongation of expanded CAG-containing transcripts, the ribosomal complex may pause on the hairpin structure formed by the elongated CAG repeat tract. Accommodation of aa-tRNA may pull the downstream mRNA into the ribosome, thus creating tension between the hairpin and slippery site. This leads to the dissociation of peptidyl-tRNA and repairs mRNA in the (−1) frame (GCA). (c) The weak interaction between the codon-anticodon GCA:CUG may result in peptidyl-tRNA drop off. (d) After unwinding of the hairpin, elongation proceeds in a new frame. (e) An increased demand for glutaminyl-tRNAGln-CUG may be the additional factor that stimulates changes in the reading frame. * - refolding hairpin.
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Related In: Results  -  Collection

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Figure 4: Speculated mechanisms of ribosomal frameshifting at CAG repeats in SCA3 and HD. Translation elongation is a cyclic process of mRNA-dependent peptide bond formation with the use of ribosomes, aminoacyl-tRNAs, energy and specific protein factors. At the start of each cycle, the complex of correct aminoacyl-tRNA and the elongation factor eEF-1AGTP are positioned in the ribosome decoding center (A site). (a) During this step, the ribosome P site binds the initiator Met-tRNA or peptidyl-tRNA. After codon recognition, followed by GTP hydrolysis, the amino acid from aminoacyl-tRNAs is transferred to the C-terminus of the growing polypeptide chain. (b) The reaction leaves an uncharged tRNA in the ribosomal P site and the new peptidyl-tRNA in the A site. Normally, during the next step, the ribosome translocates one codon forward on the mRNA, and deacylated tRNA is released from the exit (E) site of the ribosome. During translation elongation of expanded CAG-containing transcripts, the ribosomal complex may pause on the hairpin structure formed by the elongated CAG repeat tract. Accommodation of aa-tRNA may pull the downstream mRNA into the ribosome, thus creating tension between the hairpin and slippery site. This leads to the dissociation of peptidyl-tRNA and repairs mRNA in the (−1) frame (GCA). (c) The weak interaction between the codon-anticodon GCA:CUG may result in peptidyl-tRNA drop off. (d) After unwinding of the hairpin, elongation proceeds in a new frame. (e) An increased demand for glutaminyl-tRNAGln-CUG may be the additional factor that stimulates changes in the reading frame. * - refolding hairpin.
Mentions: It remains to be established whether frameshifting on CAG repeats results from an incomplete 2-base translocation event ((+2) frameshifting) or ribosome slippage by one base in the 5′ direction ((−1) frameshifting). Both these processes generate the same GCA frame encoding alanine; however, different nomenclature used by the authors may be confusing. Because frameshifting has been shown to occur in both SCA3 and HD, the most straightforward explanation is that the CAG repeat sequences of, respectively, ATXN3 and HTT are particularly susceptible to such repositions of reading frames, as experimental evidence demonstrated a higher frequency of frameshifting on longer repeats of both transcripts (26,28–30). However, as the structural requirements of RNA that induce frameshifting are not sufficiently known, it seems plausible that the hairpin structures formed by elongated CAG repeats of ATXN3 and HTT (Figure 3) (98–100) may serve as frameshifting stimulatory sequences, leading to ribosome pausing (Figure 4). Pseudoknots are a common type of stimulatory motif, but hairpin structures are also used by some viruses, e.g. HIV-1 (101,102). During translation elongation on expanded CAG repeat tracts, multiple hairpin structures may fold and unfold by moving the ribosomal complex. In investigating mechanisms of ribosomal frameshifting within repeated sequences, it would be interesting to determine whether the influence of CAA interruptions which are known to alter structure of CAG repeat hairpins (57) affects the frameshifting frequency.

Bottom Line: Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively.The contribution of unusual translation products to pathogenesis needs to be better understood.In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.

Show MeSH
Related in: MedlinePlus