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BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo
BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823046/ https://www.ncbi.nlm.nih.gov/pubmed/26515461 http://dx.doi.org/10.18632/oncotarget.5693 |
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author | Uziel, Orit Yerushalmi, Rinat Zuriano, Lital Naser, Shaden Beery, Einat Nordenberg, Jardena Lubin, Ido Adel, Yonatan Shepshelovich, Daniel Yavin, Hagai Aharon, Irit Ben Pery, Shlomit Rizel, Shulamit Pasmanik-Chor, Metsada Frumkin, Dan Lahav, Meir |
author_facet | Uziel, Orit Yerushalmi, Rinat Zuriano, Lital Naser, Shaden Beery, Einat Nordenberg, Jardena Lubin, Ido Adel, Yonatan Shepshelovich, Daniel Yavin, Hagai Aharon, Irit Ben Pery, Shlomit Rizel, Shulamit Pasmanik-Chor, Metsada Frumkin, Dan Lahav, Meir |
author_sort | Uziel, Orit |
collection | PubMed |
description | BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells. The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy. These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants. |
format | Online Article Text |
id | pubmed-4823046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-48230462016-05-03 BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo Uziel, Orit Yerushalmi, Rinat Zuriano, Lital Naser, Shaden Beery, Einat Nordenberg, Jardena Lubin, Ido Adel, Yonatan Shepshelovich, Daniel Yavin, Hagai Aharon, Irit Ben Pery, Shlomit Rizel, Shulamit Pasmanik-Chor, Metsada Frumkin, Dan Lahav, Meir Oncotarget Research Paper BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells. The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy. These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants. Impact Journals LLC 2015-10-16 /pmc/articles/PMC4823046/ /pubmed/26515461 http://dx.doi.org/10.18632/oncotarget.5693 Text en Copyright: © 2016 Uziel et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Uziel, Orit Yerushalmi, Rinat Zuriano, Lital Naser, Shaden Beery, Einat Nordenberg, Jardena Lubin, Ido Adel, Yonatan Shepshelovich, Daniel Yavin, Hagai Aharon, Irit Ben Pery, Shlomit Rizel, Shulamit Pasmanik-Chor, Metsada Frumkin, Dan Lahav, Meir BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
title | BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
title_full | BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
title_fullStr | BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
title_full_unstemmed | BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
title_short | BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
title_sort | brca1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823046/ https://www.ncbi.nlm.nih.gov/pubmed/26515461 http://dx.doi.org/10.18632/oncotarget.5693 |
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