Sir4 Deficiency Reverses Cell Senescence by Sub-Telomere Recombination

• Main Authors: Jun Liu, Xiaojing Hong, Lihui Wang, Chao-Ya Liang, Jun-Ping Liu
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Cells
• Subjects: cell senescence; senescence regulation; sub-telomeres; telomere binding protein; Sir4; Rif1
• Online Access: https://www.mdpi.com/2073-4409/10/4/778

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 <i>Saccharomyces cerevisiae</i>. The telomere protein complex Sir3/4 represses, whereas Rif1 promotes, the sub-telomere Y′ element recombination. Genetic disruption of <i>SIR4</i> 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 <i>TERRA</i>. 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.