Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
Confocal Imaging Facility, Laboratory of Cardiovascular Sciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Nucleic Acids Res. 2021 Jul 21;49(13):7389-7405. doi: 10.1093/nar/gkab538.
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.
一种受 microRNAs（miRNAs）影响的主要应激反应是衰老，这是一种由亚致死性细胞损伤引发的无限期生长停滞状态。在这里，我们通过生物信息学分析和实验验证，确定了 miR-340-5p 是一种促进细胞衰老的新型 miRNA。miR-340-5p 在多种衰老模型中含量丰富，在增殖细胞中过表达 miR-340-5p 会使其衰老。在靶 mRNA 中，miR-340-5p 显著降低了编码核膜层蛋白 B 受体（LBR）的 LBR mRNA 的水平。通过过表达 miR-340-5p 异位表达 LBR，可使异染色质在核纤层相关结构域中去抑制，从而促进衰老特征的 DNA 重复元件的表达。重要的是，过表达 miR-340-5p 增强了细胞对衰老细胞溶解化合物的敏感性，而拮抗 miR-340-5p 则减少了衰老细胞标志物的表达，并对衰老细胞诱导的细胞死亡产生了抗性。我们提出，miR-340-5p 可以被用来清除衰老细胞，以恢复组织内稳态并减轻衰老细胞在人类衰老相关疾病中的损伤。
