Reduction of lamin B receptor levels by miR-340-5p disrupts chromatin, promotes cell senescence and enhances senolysis

Abstract A 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-3...

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Published in:Nucleic acids research Vol. 49; no. 13; pp. 7389 - 7405
Main Authors: Herman, Allison B, Anerillas, Carlos, Harris, Sophia C, Munk, Rachel, Martindale, Jennifer L, Yang, Xiaoling, Mazan-Mamczarz, Krystyna, Zhang, Yongqing, Heckenbach, Indra J, Scheibye-Knudsen, Morten, De, Supriyo, Sen, Payel, Abdelmohsen, Kotb, Gorospe, Myriam
Format: Journal Article
Language:English
Published: England Oxford University Press 21.07.2021
Subjects:
Cell Line
Cell Proliferation
Cells, Cultured
Cellular Senescence - drug effects
Cellular Senescence - genetics
Gene Expression Regulation
Gene regulation, Chromatin and Epigenetics
Heterochromatin
Humans
Lamin B Receptor
MicroRNAs - metabolism
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
ISSN:0305-1048, 1362-4962, 1362-4962
Online Access:Get full text
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Summary:Abstract A 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.
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ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkab538