Effects of BRCA2 deficiency on telomere recombination in non-ALT and ALT cells.
Effects of BRCA2 deficiency on telomere recombination in non-ALT and ALT cells.
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DOI：
10.1186/2041-9414-2-9
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发表时间：
2011-12-09
期刊：
影响因子：
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通讯作者：
Slijepcevic P
中科院分区：
文献类型：
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作者：
Sapir E;Gozaly-Chianea Y;Al-Wahiby S;Ravindran S;Yasaei H;Slijepcevic P
最近的研究表明，BRCA2影响端粒的维持。有趣的是，目前正在探索分别涉及BRCA2和端粒酶的抗癌治疗方法。根据上述最近的研究，它们的联合靶向在未来的治疗发展中可能是合理的。为了研究BRCA2对这种组合靶向的影响，我们通过监测T-SCES(端粒姐妹染色单体交换)来分析端粒的重组率。我们观察到在四个BRCA2缺陷的人类细胞系中，T-SCE频率显着增加，从而表明BRCA2抑制端粒的重组。为了进一步验证这一假设，我们分析了一组带有或不带有功能性BRCA2的中国仓鼠细胞系的T-SCE频率。我们的结果表明，功能性BRCA2的引入使T-SCE的频率正常化，从而支持BRCA2抑制端粒重组的观点。鉴于ALT(替代延长端粒)阳性细胞通过重组维持端粒，我们研究了BRCA2缺失对这些细胞的影响。我们的结果表明，这种缺失导致ALT阳性细胞中T-SCE频率显著降低，但在非ALT细胞中没有。BRCA2抑制通过传统机制维持端粒的细胞中的端粒重组。此外，ALT阳性细胞中BRCA2的缺失降低了通常在这些细胞中发现的高水平的T-SCES。我们的结果可能对改进基于端粒酶的抗癌疗法具有潜在的重要意义。
Recent studies suggest that BRCA2 affects telomere maintenance. Interestingly, anti cancer treatments that involve BRCA2 and telomerase individually are currently being explored. In the light of the above recent studies their combinatorial targeting may be justified in the development of future treatments. In order to investigate effects of BRCA2 that can be explored for this combinatorial targeting we focused on the analysis of recombination rates at telomeres by monitoring T-SCEs (Telomere Sister Chromatid Exchanges). We observed a significant increase in T-SCE frequencies in four BRCA2 defective human cell lines thus suggesting that BRCA2 suppresses recombination at telomeres. To test this hypothesis further we analyzed T-SCE frequencies in a set of Chinese hamster cell lines with or without functional BRCA2. Our results indicate that introduction of functional BRCA2 normalizes frequencies of T-SCEs thus supporting the notion that BRCA2 suppresses recombination at telomeres. Given that ALT (Alternative Lengthening of Telomeres) positive cells maintain telomeres by recombination we investigated the effect of BRCA2 depletion in these cells. Our results show that this depletion causes a dramatic reduction in T-SCE frequencies in ALT positive cells, but not in non-ALT cells. BRCA2 suppresses recombination at telomeres in cells that maintain them by conventional mechanisms. Furthermore, BRCA2 depletion in ALT positive cells reduces high levels of T-SCEs normally found in these cells. Our results could be potentially important for refining telomerase-based anti-cancer therapies.