Uziel Orit, Yerushalmi Rinat, Zuriano Lital, Naser Shaden, Beery Einat, Nordenberg Jardena, Lubin Ido, Adel Yonatan, Shepshelovich Daniel, Yavin Hagai, Ben Aharon Irit, Pery Shlomit, Rizel Shulamit, Pasmanik-Chor Metsada, Frumkin Dan, Lahav Meir
The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Oncotarget. 2016 Jan 19;7(3):2433-54. doi: 10.18632/oncotarget.5693.
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.
BRCA1突变与致癌作用相关，尤其是与乳腺组织的致癌作用有关。端粒维持对于恶性转化至关重要。作为DNA修复机制的一部分，BRCA1可能与端粒生物学有关。我们通过敲低非恶性乳腺上皮细胞中BRCA1的表达，探讨了BRCA1在BRCA1/2突变携带者淋巴细胞和体外系统中端粒维持中的作用。两个系统中的结果相似。BRCA1/2突变导致端粒稳态受到干扰，单链端粒悬垂缩短，细胞间端粒长度变异性增加，以及无端粒染色体末端和端粒环的数量增加。这些变化导致DNA损伤状态增加。端粒酶活性、诱导性和表达保持不变。BRCA1突变还导致了保护素蛋白与端粒结合的变化。在携带者和体外系统中，DNMT-1水平均显著降低。携带者亚端粒区域的甲基化模式表明10号染色体存在低甲基化。一组不同基因的表达也发生了变化，其中一些可能与恶性肿瘤易感性有关。这些结果表明，BRCA基因产物在端粒长度稳态中起作用。这些扰动可能导致BRCA突变体发生恶性转化，这是合理的。
