Research Paper Advance Articles

MiR-185 targets POT1 to induce telomere dysfunction and cellular senescence

Tingting Li1, , Zhenhua Luo2, , Song Lin1, , Chujun Li1, , Shenkun Dai1, , Haoli Wang3, , Junjiu Huang1, , Wenbin Ma1, , Zhou Songyang1, , Yan Huang1, ,

  • 1 MOE Key Laboratory of Gene Function and Regulation, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
  • 2 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
  • 3 Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China

Received: January 18, 2020       Accepted: June 1, 2020       Published: July 18, 2020      

https://doi.org/10.18632/aging.103541
How to Cite

Copyright © 2020 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Protection of telomere 1 (POT1), the telomeric single-stranded DNA (ssDNA)-binding protein in the shelterin complex, has been implicated in the DNA damage response, tumorigenesis and aging. Telomere dysfunction induced by telomere deprotection could accelerate cellular senescence in primary human cells. While previous work demonstrated the biological mechanism of POT1 in aging and cancer, how POT1 is posttranscriptionally regulated remains largely unknown. To better understand the POT1 regulatory axis, we performed bioinformatic prediction, and selected candidates were further confirmed by dual-luciferase reporter assay. Collectively, our results revealed that miR-185 can significantly reduce POT1 mRNA and protein levels by directly targeting the POT1 3’-untranslated region (3’-UTR). Overexpression of miR-185 increased telomere dysfunction-induced foci (TIF) signals in both cancer cells and primary human fibroblasts. Elevated miR-185 led to telomere elongation in the telomerase-positive cell line HTC75, which was phenotypically consistent with POT1 knocking down. Moreover, miR-185 accelerated the replicative senescence process in primary human fibroblasts in a POT1-dependent manner. Interestingly, increased serum miR-185 could represent a potential aging-related biomarker. Taken together, our findings reveal miR-185 as a novel aging-related miRNA that targets POT1 and provide insight into the telomere and senescence regulatory network at both the intracellular and extracellular levels.

Abbreviations

POT1: protection of telomere 1; miRNAs: microRNAs; UTR: untranslated region; TIF: telomere dysfunction-induced foci; ATR: ataxia telangiectasia and Rad3-related kinase.