Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Telomeric repeat binding factor 2 (TRF2) is crucial for telomere maintenance, DNA damage response, and aging.
• TRF2 inhibition accelerates cellular senescence, but its post-transcriptional regulation by microRNAs (miRNAs) is largely unknown.

Purpose of the Study:

• To investigate the role of miRNAs in post-transcriptional regulation of TRF2.
• To identify specific miRNAs targeting TRF2 and their functional consequences on telomere maintenance and cellular senescence.

Main Methods:

• A large-scale luciferase reporter screen using a miRNA expression library to identify TRF2-targeting miRNAs.
• Overexpression of miR-23a in human fibroblasts.
• Assessment of TRF2 levels, telomere dysfunction-induced foci (TIFs), and cellular senescence.
• Rescue experiments with ectopic TRF2 expression.

Main Results:

• Four miRNAs were identified as targeting human TRF2, reducing endogenous TRF2 protein levels.
• miR-23a was confirmed to directly target the 3' untranslated region (3'UTR) of TRF2.
• Overexpression of miR-23a decreased telomere-bound TRF2, increased TIFs, and accelerated fibroblast senescence.
• Ectopic TRF2 expression rescued the senescence phenotype induced by miR-23a.

Conclusions:

• TRF2 is a direct and specific target of miR-23a.
• miR-23a plays a significant role in regulating telomere maintenance and promoting cellular senescence.
• This study uncovers a novel regulatory pathway involving miR-23a in telomere biology and aging.