The precise role of the BRCA1 mutation in breast carcinogenesis is not yet fully understood. BRCA1 protein is a part of the DNA damage repair machinery and may have a role in telomere biology. Telomere maintenance plays an important role in malignant transformation. The role of BRCA1 in telomeres biology was studied mainly in cancer cells in very few studies. Here we focus on the crosstalk between telomeres and BRCA1 in breast epithelial non malignant cells by knocking down its expression in these cells. Additionally, we assessed telomere length in BRCA1 mutation carriers compared to their length in normal age-matched controls.
We found that telomeres became incrementally longer in cells without BRCA1. In spite of their length, they became dysfunction, asgH2AX protein's expression increased. ChIP assay showed that TRF1 binding was increased while the other shelterin proteins of telomere remained unchanged. The methylation pattern of the sub-telomere regions of chromosomes 5 and 10 also varied: the methylation of this sub-telomeric region did not change in chromosome 5, but incrementally increased in the sub-telomere region of chromosome 10. Studies of BRCA1 carriers showed that their telomeres are shorter compared to the normal aged matched population. In addition the carriers' telomeres had shorter single strand overhang and more heterogeneous distribution of telomeres among their chromosomes.
These results show that BRCA1 has a role in telomere biology in non malignant breast epithelial cells. Its knockdown causes elongation of telomeres accompanied telomere dysfunction. TRF1 increased binding probably contributes to their elongation by a yet unknown mechanism. BRCA1 mutation carriers manifest abnormalities in telomere structure. All these perturbations may contribute to the tendency to malignant transformation in these women.
