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Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells
Triplet-repeat expansions cause several inherited human diseases. Expanded triplet-repeats are unstable in somatic cells, and tissue-specific somatic instability contributes to disease pathogenesis. In mammalian cells instability of triplet-repeats is dependent on the location of the origin of repli...
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Formato: | Texto |
Lenguaje: | English |
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Oxford University Press
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025579/ https://www.ncbi.nlm.nih.gov/pubmed/20843782 http://dx.doi.org/10.1093/nar/gkq788 |
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author | Rindler, Paul M. Bidichandani, Sanjay I. |
author_facet | Rindler, Paul M. Bidichandani, Sanjay I. |
author_sort | Rindler, Paul M. |
collection | PubMed |
description | Triplet-repeat expansions cause several inherited human diseases. Expanded triplet-repeats are unstable in somatic cells, and tissue-specific somatic instability contributes to disease pathogenesis. In mammalian cells instability of triplet-repeats is dependent on the location of the origin of replication relative to the repeat tract, supporting the ‘fork-shift’ model of repeat instability. Disease-causing triplet-repeats are transcribed, but how this influences instability remains unclear. We examined instability of the expanded (GAA•TTC)(n) sequence in mammalian cells by analyzing individual replication events directed by the SV40 origin from five different locations, in the presence and absence of doxycycline-induced transcription. Depending on the location of the SV40 origin, either no instability was observed, instability was caused by replication with no further increase due to transcription, or instability required transcription. Whereas contractions accounted for most of the observed instability, one construct showed expansions upon induction of transcription. These expansions disappeared when transcript stability was reduced via removal or mutation of a spliceable intron. These results reveal a complex interrelationship of transcription and replication in the etiology of repeat instability. While both processes may not be sufficient for the initiation of instability, transcription and/or transcript stability seem to further modulate the fork-shift model of triplet-repeat instability. |
format | Text |
id | pubmed-3025579 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-30255792011-01-24 Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells Rindler, Paul M. Bidichandani, Sanjay I. Nucleic Acids Res Genome Integrity, Repair and Replication Triplet-repeat expansions cause several inherited human diseases. Expanded triplet-repeats are unstable in somatic cells, and tissue-specific somatic instability contributes to disease pathogenesis. In mammalian cells instability of triplet-repeats is dependent on the location of the origin of replication relative to the repeat tract, supporting the ‘fork-shift’ model of repeat instability. Disease-causing triplet-repeats are transcribed, but how this influences instability remains unclear. We examined instability of the expanded (GAA•TTC)(n) sequence in mammalian cells by analyzing individual replication events directed by the SV40 origin from five different locations, in the presence and absence of doxycycline-induced transcription. Depending on the location of the SV40 origin, either no instability was observed, instability was caused by replication with no further increase due to transcription, or instability required transcription. Whereas contractions accounted for most of the observed instability, one construct showed expansions upon induction of transcription. These expansions disappeared when transcript stability was reduced via removal or mutation of a spliceable intron. These results reveal a complex interrelationship of transcription and replication in the etiology of repeat instability. While both processes may not be sufficient for the initiation of instability, transcription and/or transcript stability seem to further modulate the fork-shift model of triplet-repeat instability. Oxford University Press 2011-01 2010-09-14 /pmc/articles/PMC3025579/ /pubmed/20843782 http://dx.doi.org/10.1093/nar/gkq788 Text en © The Author(s) 2010. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.5 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Rindler, Paul M. Bidichandani, Sanjay I. Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
title | Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
title_full | Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
title_fullStr | Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
title_full_unstemmed | Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
title_short | Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
title_sort | role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025579/ https://www.ncbi.nlm.nih.gov/pubmed/20843782 http://dx.doi.org/10.1093/nar/gkq788 |
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