Human telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been determined. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. Our findings suggest that the persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.

人类端粒由端粒重复结合蛋白 TRF1 和 TRF2 结合。人类细胞中的端粒缩短会导致 DNA 损伤反应，从而发出复制衰老的信号。虽然端粒缩短时 TRF2 负载不足会导致衰老过程中的 DNA 损伤反应，但 TRF1 对衰老诱导的贡献尚未确定。在这里，我们表明，与 TRF2 缺陷介导的 DNA 损伤诱导相反，TRF1 缺陷起到保护作用，限制亚端粒重组诱导的 DNA 损伤。缩短的端粒募集的 TRF1 不足，因此端聚合酶 1 不足以解决姐妹端粒的内聚力。我们的研究结果表明，持久的内聚力可以保护短端粒免遭不适当的重组。最终，在最后的分裂中，端粒不再能够保持内聚力，随后发生亚端粒复制。因此，TRF1 的逐渐丧失以及伴随端粒缩短而发生的持续内聚力确保了复制衰老的可测量方法。