4.6 Article

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

Journal

FRONTIERS IN PHYSIOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2021.726345

Keywords

growth differentiation factor 11; telomere length; TERT; TERC; telomerase activity; Smad2; replicative cellular senescence

Categories

Funding

  1. Ningxia Key RD Program [2019BFH02012]
  2. National Key R&D Program of China [2017YFA0104900, BZZ19J005]
  3. National Natural Science Foundation of China [81971144, 81571170, 31471021]

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The study confirmed the crucial role of GDF11 in maintaining telomere length in cells, and demonstrated that the lack of GDF11 leads to telomere shortening and reduced telomerase activity, indicating the significant impact of GDF11 on the cell cycle.
Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11(KO) cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.

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