title: Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression.
abstract: Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post-translationally, whether microRNAs (miRNAs) also participate in post-transcriptionally modulating TRF2 levels remains largely unknown. To better understand the regulatory pathways that control TRF2, we carried out a large-scale luciferase reporter screen using a miRNA expression library and identified four miRNAs that could target human TRF2 and significantly reduce the level of endogenous TRF2 proteins. In particular, our data revealed that miR-23a could directly target the 3' untranslated region (3'UTR) of TRF2. Overexpression of miR-23a not only reduced telomere-bound TRF2 and increased telomere dysfunction-induced foci (TIFs), but also accelerated senescence of human fibroblast cells, which could be rescued by ectopically expressed TRF2. Our findings demonstrate that TRF2 is a specific target of miR-23a, and uncover a previously unknown role for miR-23a in telomere regulation and cellular senescence.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China; SYSU-BCM Joint Research Center for Biomedical Sciences and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Luo
authors.forename: Xuyang
authors.initials: X
authors.lastname: Feng
authors.forename: Haoli
authors.initials: H
authors.lastname: Wang
authors.forename: Weiyi
authors.initials: W
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ma
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Junjiu
authors.initials: J
authors.lastname: Huang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Songyang
mesh_terms: D049109:Cell Proliferation / Q000502:physiology*; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2
keywords: TRF2; cellular senescence; luciferase reporter screen; miR-23a; telomere dysfunction