title: BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo.
abstract: 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.
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Uziel
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Institute of Oncology, Davidoff Cancer Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Rinat
authors.initials: R
authors.lastname: Yerushalmi
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Lital
authors.initials: L
authors.lastname: Zuriano
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Shaden
authors.initials: S
authors.lastname: Naser
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Beery
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Jardena
authors.initials: J
authors.lastname: Nordenberg
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Lubin
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Internal Medicine A, Beilinson Medical Center, Petah Tikva, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Adel
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Internal Medicine A, Beilinson Medical Center, Petah Tikva, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Shepshelovich
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Internal Medicine A, Beilinson Medical Center, Petah Tikva, Israel.
authors.forename: Hagai
authors.initials: H
authors.lastname: Yavin
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Institute of Oncology, Davidoff Cancer Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Ben Aharon
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Institute of Oncology, Davidoff Cancer Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Pery
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Institute of Oncology, Davidoff Cancer Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Rizel
authors.affiliation: Bioinformatics Unit, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: Nucleix Ltd. Tel Aviv, Petah Tikva, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Frumkin
authors.affiliation: The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Institute of Hematology, Davidoff Cancer Center, Beilinson Medical Center, Petah Tikva, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Lahav
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D019098:Telomerase; D016615:Telomere / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D019098:Telomerase
keywords: BRCA1/2; malignant transformation; telomere homeostasis; telomeres