BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo
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Orit Uziel1,2,*, Rinat Yerushalmi2,3,*, Lital Zuriano1, Shaden Naser1, Einat Beery1, Jardena Nordenberg1,2, Ido Lubin1,2, Yonatan Adel2,6, Daniel Shepshelovich2,6, Hagai Yavin2,6, Irit Ben Aharon2,3, Shlomit Pery2,3, Shulamit Rizel2,3, Metsada Pasmanik-Chor4, Dan Frumkin5, Meir Lahav1,2,7
1The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel
2Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3Institute of Oncology, Davidoff Cancer Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel
4Bioinformatics Unit, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
5Nucleix Ltd. Tel Aviv, Petah Tikva, Israel
6Internal Medicine A, Beilinson Medical Center, Petah Tikva, Israel
7Institute of Hematology, Davidoff Cancer Center, Beilinson Medical Center, Petah Tikva, Israel
*These authors have contributed equally to this work
Meir Lahav, e-mail: [email protected]
Keywords: telomeres, BRCA1/2, malignant transformation, telomere homeostasis
Received: April 08, 2015 Accepted: October 06, 2015 Published: October 16, 2015
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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