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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Vydáno v:	Nucleic acids research Ročník 49; číslo 13; s. 7389 - 7405
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Oxford University Press 21.07.2021
Témata:	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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkab538