Persistent telomere cohesion protects aged cells from premature senescence

Abstract

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.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.

Nuclear PARPs and genome integrity

“…Could the population of shortened telomeres with insufficient TRF1 contribute to persistent telomere cohesion as in aging cells? Indeed, introduction of telomerase into ALT cells rescues the persistent cohesion, linking the phenotype to shortened telomeres (Azarm et al 2020). Overexpression of wild-type TRF1, but not a tankyrasebinding-site mutant, recruits tankyrase 1 to telomeres, forces resolution of cohesion, and leads to similar phenotypes in ALT as in aging cells: subtelomere recombination, DNA damage, and (in checkpoint-proficient U2OS ALT cells) senescence (Azarm et al 2020).…”

“…Thus, in contrast to telomere length maintenance where either tankyrase 1 or tankyrase 2 is sufficient, resolution of telomere cohesion requires both tankyrase 1 and tankyrase 2 (Bhardwaj et al 2017). CRISPR-generated mutation of the tankyrase-binding site in TRF1 (from 13-RGCADG to RGDADP) leads to persistent telomere cohesion, indicating that TRF1-mediated recruitment of tankyrase is required for resolution (Azarm et al 2020).…”

“…Tankyrase levels are not reduced in aging cells, yet overexpression of PARP-active tankyrase 1 rescues the persistent telomere cohesion, hinting at a mechanism that prevents endogenous tankyrase from acting at telomeres in these aged cells (Kim and Smith 2014). Indeed, a recent study shows that shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion (Azarm et al 2020). Overexpression of wild-type TRF1, but not a tankyrase-binding site mutant (from 13-RGCADG to RGDAAA), promotes recruitment of tankyrase 1 to aging cell telomeres and forces resolution of cohesion.…”

“…Overexpression of wild-type TRF1, but not a tankyrase-binding site mutant (from 13-RGCADG to RGDAAA), promotes recruitment of tankyrase 1 to aging cell telomeres and forces resolution of cohesion. Surprisingly, persistent cohesion is beneficial to aging cells; forcing resolution results in deleterious phenotypes: excessive interchromosomal subtelomere recombination, DNA damage, and premature activation of checkpoint-mediated senescence (Azarm et al 2020). The limited recruitment of tankyrase at shortened telomeres promotes persistent telomere cohesion, protecting chromosome ends from engaging in damage-inducing subtelomere recombination that signals premature cell cycle arrest.…”

“…A noncanonical role for the PAR-binding macroH2A1.1 In both aging normal cells and ALT cancer cells, reduced TRF1 at shortened telomeres limits tankyrase 1 recruitment (Ramamoorthy and Smith 2015;Azarm et al 2020). There appears to be an additional mechanism (at least in ALT cells) that acts directly through tankyrase 1.…”