Authors: Allison B Herman, Carlos Anerillas, Sophia C Harris, Rachel Munk, Jennifer L Martindale, Xiaoling Yang, Krystyna Mazan-Mamczarz, Yongqing Zhang, Indra J Heckenbach, Morten Scheibye-Knudsen, Supriyo De, Payel Sen, Kotb Abdelmohsen, Myriam Gorospe
Published: 2021-06-10
DOI: 10.1093/nar/gkab538
Source: Full article
AbstractA major stress response influenced by microRNAs (miRNAs) is senescence, a state of indefinite growth arrest triggered by sublethal cell damage. Here, through bioinformatic analysis and experimental validation, we identified miR-340-5p as a novel miRNA that foments cellular senescence. miR-340-5p was highly abundant in diverse senescence models, and miR-340-5p overexpression in proliferating cells rendered them senescent. Among the target mRNAs, miR-340-5p prominently reduced the levels of LBR mRNA, encoding lamin B receptor (LBR). Loss of LBR by ectopic overexpression of miR-340-5p derepressed heterochromatin in lamina-associated domains, promoting the expression of DNA repetitive elements characteristic of senescence. Importantly, overexpressing miR-340-5p enhanced cellular sensitivity to senolytic compounds, while antagonization of miR-340-5p reduced senescent cell markers and engendered resistance to senolytic-induced cell death. We propose that miR-340-5p can be exploited for removing senescent cells to restore tissue homeostasis and mitigate damage by senescent cells in pathologies of human aging.