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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
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.
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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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