Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.
G3 (Bethesda). 2011 Aug;1(3):197-208. doi: 10.1534/g3.111.000216. Epub 2011 Aug 1.
In telomerase-deficient yeast cells, like equivalent mammalian cells, telomeres shorten over many generations until a period of senescence/crisis is reached. After this, a small fraction of cells can escape senescence, principally using recombination-dependent mechanisms. To investigate the pathways that affect entry into and recovery from telomere-driven senescence, we combined a gene deletion disrupting telomerase (est1Δ) with the systematic yeast deletion collection and measured senescence characteristics in high-throughput assays. As expected, the vast majority of gene deletions showed no strong effects on entry into/exit from senescence. However, around 200 gene deletions behaving similarly to a rad52Δest1Δ archetype (rad52Δ affects homologous recombination) accelerated entry into senescence, and such cells often could not recover growth. A smaller number of strains similar to a rif1Δest1Δ archetype (rif1Δ affects proteins that bind telomeres) accelerated entry into senescence but also accelerated recovery from senescence. Our genome-wide analysis identifies genes that affect entry into and/or exit from telomere-initiated senescence and will be of interest to those studying telomere biology, replicative senescence, cancer, and ageing. Our dataset is complementary to other high-throughput studies relevant to telomere biology, genetic stability, and DNA damage responses.
在端粒酶缺陷的酵母细胞中，与相当的哺乳动物细胞一样，端粒在许多代中缩短，直到达到衰老/危机期。在此之后，一小部分细胞可以逃避衰老，主要使用依赖重组的机制。为了研究影响进入和恢复端粒驱动衰老的途径，我们将破坏端粒酶的基因缺失（est1Δ）与系统酵母缺失集合相结合，并在高通量测定中测量衰老特征。正如预期的那样，绝大多数基因缺失对进入/退出衰老没有强烈影响。然而，大约 200 个基因缺失类似于 rad52Δest1Δ 原型（rad52Δ 影响同源重组）加速进入衰老，并且这些细胞通常无法恢复生长。数量较少的菌株类似于 rif1Δest1Δ 原型（rif1Δ 影响与端粒结合的蛋白质）加速进入衰老，但也加速了从衰老中恢复。我们的全基因组分析确定了影响进入和/或退出端粒起始衰老的基因，这将对研究端粒生物学、复制性衰老、癌症和衰老的人感兴趣。我们的数据集与其他与端粒生物学、遗传稳定性和 DNA 损伤反应相关的高通量研究互补。
