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Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics
BACKGROUND: Cells adapt to various chronic toxic exposures in a multitude of ways to minimize further damage and maximize their growth potential. Expression of L1 elements in the human genome can be greatly deleterious to cells, generating numerous double strand breaks (DSBs). Cells have been report...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164224/ https://www.ncbi.nlm.nih.gov/pubmed/20979631 http://dx.doi.org/10.1186/1759-8753-1-22 |
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author | Wallace, Nicholas A Belancio, Victoria P Faber, Zach Deininger, Prescott |
author_facet | Wallace, Nicholas A Belancio, Victoria P Faber, Zach Deininger, Prescott |
author_sort | Wallace, Nicholas A |
collection | PubMed |
description | BACKGROUND: Cells adapt to various chronic toxic exposures in a multitude of ways to minimize further damage and maximize their growth potential. Expression of L1 elements in the human genome can be greatly deleterious to cells, generating numerous double strand breaks (DSBs). Cells have been reported to respond to chronic DSBs by altering the repair of these breaks, including increasing the rate of homology independent DSB repair. Retrotransposition is strongly affected by proteins involved in DSB repair. Therefore, L1 expression has the potential to be a source of chronic DSBs and thus bring about the changes in cellular environment that could ultimately restrict its own retrotransposition. RESULTS: We demonstrate that constitutive L1 expression leads to quicker DSB repair and decreases in the retrotransposition potential of L1 and other retrotransposons dependent on L1 expression for their mobility. This cellular adaptation results in reduced sensitivity to L1 induced toxicity. These effects can be induced by constitutive expression of the functional L1 ORF2 alone, but not by the constitutive expression of an L1 open reading frame 2 with mutations to its endonuclease and reverse transcriptase domains. This adaptation correlates with the relative activity of the L1 introduced into the cells. CONCLUSIONS: The increased number of DSBs resulting from constitutive expression of L1 results in a more rapid rate of repair. The cellular response to this L1 expression also results in attenuation of retrotransposition and reduced sensitivity of the cells to negative consequences of L1 ORF2 expression. The influence does not appear to be through RNA interference. We believe that the increased rate of DSB repair is the most likely cause of the attenuation of retrotransposition. These alterations act as a fail safe mechanism that allows cells to escape the toxicity associated with the unchecked L1 expression. This gives cells that overexpress L1, such as tumor cells, the ability to survive the high levels of expression. However, the increased rate of break repair may come at the cost of accuracy of repair of the lesion, resulting in increased genomic instability. |
format | Online Article Text |
id | pubmed-3164224 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-31642242011-09-02 Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics Wallace, Nicholas A Belancio, Victoria P Faber, Zach Deininger, Prescott Mob DNA Research BACKGROUND: Cells adapt to various chronic toxic exposures in a multitude of ways to minimize further damage and maximize their growth potential. Expression of L1 elements in the human genome can be greatly deleterious to cells, generating numerous double strand breaks (DSBs). Cells have been reported to respond to chronic DSBs by altering the repair of these breaks, including increasing the rate of homology independent DSB repair. Retrotransposition is strongly affected by proteins involved in DSB repair. Therefore, L1 expression has the potential to be a source of chronic DSBs and thus bring about the changes in cellular environment that could ultimately restrict its own retrotransposition. RESULTS: We demonstrate that constitutive L1 expression leads to quicker DSB repair and decreases in the retrotransposition potential of L1 and other retrotransposons dependent on L1 expression for their mobility. This cellular adaptation results in reduced sensitivity to L1 induced toxicity. These effects can be induced by constitutive expression of the functional L1 ORF2 alone, but not by the constitutive expression of an L1 open reading frame 2 with mutations to its endonuclease and reverse transcriptase domains. This adaptation correlates with the relative activity of the L1 introduced into the cells. CONCLUSIONS: The increased number of DSBs resulting from constitutive expression of L1 results in a more rapid rate of repair. The cellular response to this L1 expression also results in attenuation of retrotransposition and reduced sensitivity of the cells to negative consequences of L1 ORF2 expression. The influence does not appear to be through RNA interference. We believe that the increased rate of DSB repair is the most likely cause of the attenuation of retrotransposition. These alterations act as a fail safe mechanism that allows cells to escape the toxicity associated with the unchecked L1 expression. This gives cells that overexpress L1, such as tumor cells, the ability to survive the high levels of expression. However, the increased rate of break repair may come at the cost of accuracy of repair of the lesion, resulting in increased genomic instability. BioMed Central 2010-10-27 /pmc/articles/PMC3164224/ /pubmed/20979631 http://dx.doi.org/10.1186/1759-8753-1-22 Text en Copyright ©2010 Wallace et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Wallace, Nicholas A Belancio, Victoria P Faber, Zach Deininger, Prescott Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics |
title | Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics |
title_full | Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics |
title_fullStr | Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics |
title_full_unstemmed | Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics |
title_short | Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics |
title_sort | feedback inhibition of l1 and alu retrotransposition through altered double strand break repair kinetics |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164224/ https://www.ncbi.nlm.nih.gov/pubmed/20979631 http://dx.doi.org/10.1186/1759-8753-1-22 |
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