Reversibility of replicative senescence in Saccharomyces cerevisiae: Effect of homologous recombination and cell cycle checkpoints
Reversibility of replicative senescence in Saccharomyces cerevisiae: Effect of homologous recombination and cell cycle checkpoints
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DOI：
10.1016/j.dnarep.2011.10.003
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发表时间：
2012-01-02
期刊：
影响因子：
3.8
通讯作者：
Lewis, L. Kevin
中科院分区：
文献类型：
--
作者：
Becerra, Sandra C.;Thambugala, Hiranthi T.;Lewis, L. Kevin
在培养中生长的原代人体体细胞分裂有限次，在周期停止之前表现出新陈代谢和形态的渐进性变化。这种端粒引发的细胞衰老是因为细胞停止了端粒酶的产生，端粒酶是稳定染色体末端所需的DNA聚合酶。端粒酶缺陷的酿酒酵母细胞经历了类似的过程，大多数细胞在大约60代后停止生长。在目前的研究中，我们证明衰老在很大程度上是可逆的。端粒酶(EST2)在生长停滞细胞中的表达重新激活，导致细胞周期的恢复和衰老细胞特性的逆转。在衰老的单倍体细胞与端粒酶熟练的细胞交配形成稳定的二倍体后，也观察到了挽救作用。虽然DNA损伤检查点反应突变体(MEC3和/或rad24细胞)的衰老是可逆的，但重组缺陷的rad52突变体在端粒酶重新激活后存活率仍然很低。在挽救的est2细胞中，端粒长度最初是野生型细胞的一半，但在端粒酶存在的情况下，通过繁殖大约70代可以恢复正常。这些结果对可能的衰老模型提出了限制，并表明大多数细胞，尽管发生了大体的形态变化和短的端粒切除，但不会经历致命的DNA损伤，并变得不可逆转地走向死亡。(C)2011爱思唯尔B.V.保留所有权利。
Primary human somatic cells grown in culture divide a finite number of times, exhibiting progressive changes in metabolism and morphology before cessation of cycling. This telomere-initiated cellular senescence occurs because cells have halted production of telomerase, a DNA polymerase required for stabilization of chromosome ends. Telomerase-deficient Saccharomyces cerevisiae cells undergo a similar process, with most cells arresting growth after approximately 60 generations. In the current study we demonstrate that senescence is largely reversible. Reactivation of telomerase (EST2) expression in the growth-arrested cells led to resumption of cycling and reversal of senescent cell characteristics. Rescue was also observed after mating of senescent haploid cells with telomerase-proficient cells to form stable diploids. Although senescence was reversible in DNA damage checkpoint response mutants (mec3 and/or rad24 cells), survival of recombination-defective rad52 mutants remained low after telomerase reactivation. Telomere lengths in rescued est2 cells were initially half those of wildtype cells, but could be restored to normal by propagation for similar to 70 generations in the presence of telomerase. These results place limitations on possible models for senescence and indicate that most cells, despite gross morphological changes and short, resected telomeres, do not experience lethal DNA damage and become irreversibly committed to death. (C) 2011 Elsevier B.V. All rights reserved.