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Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q

Trinucleotide repeat (TNR) instability is associated with human neurodegenerative diseases and cancer. Recent studies have pointed out that DNA base excision repair (BER) mediated by DNA polymerase β (pol β) plays a crucial role in governing somatic TNR instability in a damage-location dependent man...

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Autores principales: Ren, Yaou, Lai, Yanhao, Laverde, Eduardo E., Lei, Ruipeng, Rein, Hayley L., Liu, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419657/
https://www.ncbi.nlm.nih.gov/pubmed/28475635
http://dx.doi.org/10.1371/journal.pone.0177299
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author Ren, Yaou
Lai, Yanhao
Laverde, Eduardo E.
Lei, Ruipeng
Rein, Hayley L.
Liu, Yuan
author_facet Ren, Yaou
Lai, Yanhao
Laverde, Eduardo E.
Lei, Ruipeng
Rein, Hayley L.
Liu, Yuan
author_sort Ren, Yaou
collection PubMed
description Trinucleotide repeat (TNR) instability is associated with human neurodegenerative diseases and cancer. Recent studies have pointed out that DNA base excision repair (BER) mediated by DNA polymerase β (pol β) plays a crucial role in governing somatic TNR instability in a damage-location dependent manner. It has been shown that the activities and function of BER enzymes and cofactors can be modulated by their polymorphic variations. This could alter the function of BER in regulating TNR instability. However, the roles of BER polymorphism in modulating TNR instability remain to be elucidated. A previous study has shown that a pol β polymorphic variant, polβR137Q is associated with cancer due to its impaired polymerase activity and its deficiency in interacting with a BER cofactor, proliferating cell nuclear antigen (PCNA). In this study, we have studied the effect of the pol βR137Q variant on TNR instability. We showed that pol βR137Q exhibited weak DNA synthesis activity to cause TNR deletion during BER. We demonstrated that similar to wild-type pol β, the weak DNA synthesis activity of pol βR137Q allowed it to skip over a small loop formed on the template strand, thereby facilitating TNR deletion during BER. Our results further suggest that carriers with pol βR137Q polymorphic variant may not exhibit an elevated risk of developing human diseases that are associated with TNR instability.
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spelling pubmed-54196572017-05-14 Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q Ren, Yaou Lai, Yanhao Laverde, Eduardo E. Lei, Ruipeng Rein, Hayley L. Liu, Yuan PLoS One Research Article Trinucleotide repeat (TNR) instability is associated with human neurodegenerative diseases and cancer. Recent studies have pointed out that DNA base excision repair (BER) mediated by DNA polymerase β (pol β) plays a crucial role in governing somatic TNR instability in a damage-location dependent manner. It has been shown that the activities and function of BER enzymes and cofactors can be modulated by their polymorphic variations. This could alter the function of BER in regulating TNR instability. However, the roles of BER polymorphism in modulating TNR instability remain to be elucidated. A previous study has shown that a pol β polymorphic variant, polβR137Q is associated with cancer due to its impaired polymerase activity and its deficiency in interacting with a BER cofactor, proliferating cell nuclear antigen (PCNA). In this study, we have studied the effect of the pol βR137Q variant on TNR instability. We showed that pol βR137Q exhibited weak DNA synthesis activity to cause TNR deletion during BER. We demonstrated that similar to wild-type pol β, the weak DNA synthesis activity of pol βR137Q allowed it to skip over a small loop formed on the template strand, thereby facilitating TNR deletion during BER. Our results further suggest that carriers with pol βR137Q polymorphic variant may not exhibit an elevated risk of developing human diseases that are associated with TNR instability. Public Library of Science 2017-05-05 /pmc/articles/PMC5419657/ /pubmed/28475635 http://dx.doi.org/10.1371/journal.pone.0177299 Text en © 2017 Ren et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ren, Yaou
Lai, Yanhao
Laverde, Eduardo E.
Lei, Ruipeng
Rein, Hayley L.
Liu, Yuan
Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q
title Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q
title_full Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q
title_fullStr Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q
title_full_unstemmed Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q
title_short Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q
title_sort modulation of trinucleotide repeat instability by dna polymerase β polymorphic variant r137q
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419657/
https://www.ncbi.nlm.nih.gov/pubmed/28475635
http://dx.doi.org/10.1371/journal.pone.0177299
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