Bourgeron Thibault, Xu Zhou, Doumic Marie, Teixeira Maria Teresa
INRIA Paris-Rocquencourt, Domaine de Voluceau, BP 105, 78153 Le Chesnay, France. UPMC University of Paris 6, JL Lions Lab., 4 place Jussieu, 75005 Paris, France.
Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France.
Sci Rep. 2015 Oct 15;5:15326. doi: 10.1038/srep15326.
In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental data obtained from individual lineages of senescent Saccharomyces cerevisiae cells, we decompose the sources of senescence heterogeneity into interclonal and intraclonal components, and show that the latter is based on the asymmetry of the telomere replication mechanism. We also evidence telomere rank-switching events with distinct frequencies in short-lived versus long-lived lineages, revealing that telomere shortening dynamics display important variations. Thus, the intrinsic heterogeneity of replicative senescence and its consequences find their roots in the asymmetric structure of telomeres.
在真核生物中，端粒酶的缺失会导致端粒缩短，最终导致复制性衰老，这是一种阻止细胞进一步分裂的停滞状态。虽然复制性衰老主要由端粒长度控制，但其起始的异质性尚未得到很好的理解。本研究基于端粒复制和缩短的分子机制提出了一个数学模型，以解释这种异质性的原因。通过对从衰老酿酒酵母细胞的各个谱系获得的实验数据进行拟合模拟，我们将衰老异质性的来源分解为克隆间和克隆内成分，并表明后者基于端粒复制机制的不对称性。我们还证明了短寿命与长寿命谱系中端粒等级转换事件的频率不同，揭示了端粒缩短动态存在重要差异。因此，复制性衰老的内在异质性及其后果源于端粒的不对称结构。
