Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou 311121, China.
Department of Immunology, Faculty of Medicine, Monash University, Prahran, VIC 3181, Australia.
Cells. 2021 Apr 1;10(4):778. doi: 10.3390/cells10040778.
Telomere shortening results in cellular senescence and the regulatory mechanisms remain unclear. Here, we report that the sub-telomere regions facilitate telomere lengthening by homologous recombination, thereby attenuating senescence in yeast . The telomere protein complex Sir3/4 represses, whereas Rif1 promotes, the sub-telomere Y' element recombination. Genetic disruption of increases Y' element abundance and rescues telomere-shortening-induced senescence in a Rad51-dependent manner, indicating a sub-telomere regulatory switch in regulating organismal senescence by DNA recombination. Inhibition of the sub-telomere recombination requires Sir4 binding to perinuclear protein Mps3 for telomere perinuclear localization and transcriptional repression of the telomeric repeat-containing RNA . Furthermore, Sir4 repression of Y' element recombination is negatively regulated by Rif1 that mediates senescence-evasion induced by Sir4 deficiency. Thus, our results demonstrate a dual opposing control mechanism of sub-telomeric Y' element recombination by Sir3/4 and Rif1 in the regulation of telomere shortening and cell senescence.
端粒缩短导致细胞衰老，但其调控机制尚不清楚。在这里，我们报告亚端粒区域通过同源重组促进端粒延长，从而减轻酵母中的衰老。端粒蛋白复合物 Sir3/4 抑制，而 Rif1 促进亚端粒 Y' 元件重组。破坏增加 Y' 元件的丰度，并以 Rad51 依赖的方式拯救端粒缩短诱导的衰老，表明通过 DNA 重组调节生物体衰老的亚端粒调控开关。亚端粒重组的抑制需要 Sir4 与核周蛋白 Mps3 结合，以使端粒核周定位，并抑制端粒重复 RNA 的转录。此外， Rif1 介导 Sir4 缺陷诱导的衰老逃避负调控 Sir4 对 Y' 元件重组的抑制。因此，我们的结果表明 Sir3/4 和 Rif1 通过双相反抗控制机制调节端粒缩短和细胞衰老中亚端粒 Y' 元件的重组。
