Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Halda Therapeutics, New Haven, CT 06511, USA.
Cell Rep. 2023 Oct 31;42(10):113235. doi: 10.1016/j.celrep.2023.113235. Epub 2023 Oct 14.
Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase tankyrase to telomeres. In human aged cells, due to insufficient recruitment of TRF1/tankyrase to shortened telomeres, sisters remain cohered in mitosis. This persistent cohesion plays a protective role, but the mechanism by which sisters remain cohered is not well understood. Here we show that telomere repeat-containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43, is required for repression of TERRA R-loops. Persistent telomere cohesion in C19orf43-depleted cells is counteracted by RNaseH1, confirming that RNA-DNA hybrids hold sisters together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduces DNA damage and delays replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop-repressing machinery permits a controlled onset of senescence.
人源细胞中端粒姐妹体的黏合解离依赖于 TRF1 介导的聚 ADP-核糖基转移酶 Tankyrase 招募至端粒。在衰老细胞中，由于 TRF1/Tankyrase 向缩短的端粒的募集不足，姐妹染色单体在有丝分裂中保持黏合。这种持续的黏合具有保护作用，但姐妹染色单体保持黏合的机制尚不清楚。本研究表明，端粒重复 RNA（TERRA）通过 RNA-DNA 杂交（R 环）结构将端粒姐妹体保持在一起。本研究表明，Tankyrase 相互作用的伙伴，RNA 结合蛋白 C19orf43，对于 TERRA R 环的抑制是必需的。C19orf43 耗竭细胞中持续的端粒黏合被 RNaseH1 逆转，证实 RNA-DNA 杂合体能将姐妹体保持在一起。与持续端粒黏合的保护作用一致，衰老细胞中 C19orf43 的耗竭减少了 DNA 损伤并延迟了复制性衰老。本研究提出，缩短的端粒固有地不能募集 R 环抑制机制，从而允许衰老的可控起始。
