BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalitiesin vitroandin vivo

// Orit Uziel 1, 2, * , Rinat Yerushalmi 2, 3, * , Lital Zuriano 1 , Shaden Naser 1 , Einat Beery 1 , Jardena Nordenberg 1, 2 , Ido Lubin 1, 2 , Yonatan Adel 2, 6 , Daniel Shepshelovich 2, 6 , Hagai Yavin 2, 6 , Irit Ben Aharon 2, 3 , Shlomit Pery 2, 3 , Shulamit Rizel 2, 3 , Metsada Pasmanik-Chor 4 , Dan Frumkin 5 , Meir Lahav 1, 2, 7 1 The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel 2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 3 Institute of Oncology, Davidoff Cancer Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel 4 Bioinformatics Unit, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel 5 Nucleix Ltd. Tel Aviv, Petah Tikva, Israel 6 Internal Medicine A, Beilinson Medical Center, Petah Tikva, Israel 7 Institute of Hematology, Davidoff Cancer Center, Beilinson Medical Center, Petah Tikva, Israel * These authors have contributed equally to this work Correspondence to: Meir Lahav, e-mail: mlahav@post.tau.ac.il Keywords: telomeres, BRCA1/2, malignant transformation, telomere homeostasis Received: April 08, 2015      Accepted: October 06, 2015      Published: October 16, 2015 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.