Cargando…
RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders
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 boundary between such classifications has recently been blurred by the disc...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231732/ https://www.ncbi.nlm.nih.gov/pubmed/25217582 http://dx.doi.org/10.1093/nar/gku794 |
_version_ | 1782344476333703168 |
---|---|
author | Wojciechowska, Marzena Olejniczak, Marta Galka-Marciniak, Paulina Jazurek, Magdalena Krzyzosiak, Wlodzimierz J. |
author_facet | Wojciechowska, Marzena Olejniczak, Marta Galka-Marciniak, Paulina Jazurek, Magdalena Krzyzosiak, Wlodzimierz J. |
author_sort | Wojciechowska, Marzena |
collection | PubMed |
description | 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 boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. 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. |
format | Online Article Text |
id | pubmed-4231732 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-42317322014-11-21 RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders Wojciechowska, Marzena Olejniczak, Marta Galka-Marciniak, Paulina Jazurek, Magdalena Krzyzosiak, Wlodzimierz J. Nucleic Acids Res Survey and Summary 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 boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. 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. Oxford University Press 2014-10-29 2014-09-12 /pmc/articles/PMC4231732/ /pubmed/25217582 http://dx.doi.org/10.1093/nar/gku794 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Survey and Summary Wojciechowska, Marzena Olejniczak, Marta Galka-Marciniak, Paulina Jazurek, Magdalena Krzyzosiak, Wlodzimierz J. RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
title | RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
title_full | RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
title_fullStr | RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
title_full_unstemmed | RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
title_short | RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
title_sort | ran translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders |
topic | Survey and Summary |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231732/ https://www.ncbi.nlm.nih.gov/pubmed/25217582 http://dx.doi.org/10.1093/nar/gku794 |
work_keys_str_mv | AT wojciechowskamarzena rantranslationandframeshiftingastranslationalchallengesatsimplerepeatsofhumanneurodegenerativedisorders AT olejniczakmarta rantranslationandframeshiftingastranslationalchallengesatsimplerepeatsofhumanneurodegenerativedisorders AT galkamarciniakpaulina rantranslationandframeshiftingastranslationalchallengesatsimplerepeatsofhumanneurodegenerativedisorders AT jazurekmagdalena rantranslationandframeshiftingastranslationalchallengesatsimplerepeatsofhumanneurodegenerativedisorders AT krzyzosiakwlodzimierzj rantranslationandframeshiftingastranslationalchallengesatsimplerepeatsofhumanneurodegenerativedisorders |