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一种有缺陷的剪接机制通过 MDM4 可变剪接促进衰老。

A defective splicing machinery promotes senescence through MDM4 alternative splicing.

机构信息

Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada.

出版信息

Aging Cell. 2024 Nov;23(11):e14301. doi: 10.1111/acel.14301. Epub 2024 Aug 8.

DOI:10.1111/acel.14301
PMID:39118304
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11561654/
Abstract

Defects in the splicing machinery are implicated in various diseases, including cancer. We observed a general reduction in the expression of spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced, and telomere uncapping-induced senescence. Supporting the view that defective splicing contributes to senescence, splicing inhibitors herboxidiene, and pladienolide B induced senescence in normal and cancer cell lines. Furthermore, depleting individual spliceosome components also promoted senescence. All senescence types were associated with an alternative splicing transition from the MDM4-FL variant to MDM4-S. The MDM4 splicing shift was reproduced when splicing was inhibited, and spliceosome components were depleted. While decreasing the level of endogenous MDM4 promoted senescence and cell survival independently of the MDM4-S expression status, cell survival was also improved by increasing MDM4-S. Overall, our work establishes that splicing defects modulate the alternative splicing of MDM4 to promote senescence and cell survival.

摘要

剪接机制的缺陷与各种疾病有关，包括癌症。我们观察到在经历复制性、应激诱导和端粒去帽诱导衰老的人类细胞系中，剪接体成分和剪接调节剂的表达普遍降低。支持剪接缺陷导致衰老的观点，剪接抑制剂海兔毒素和 pladienolide B 在正常和癌细胞系中诱导衰老。此外，耗尽单个剪接体成分也促进了衰老。所有类型的衰老都与 MDM4-FL 变体到 MDM4-S 的可变剪接转换有关。当抑制剪接并耗尽剪接体成分时，会再现 MDM4 剪接转变。虽然降低内源性 MDM4 水平可以独立于 MDM4-S 表达状态促进衰老和细胞存活，但增加 MDM4-S 也可以改善细胞存活。总的来说，我们的工作表明剪接缺陷调节 MDM4 的可变剪接以促进衰老和细胞存活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/f7bcecb4ae95/ACEL-23-e14301-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/fdc4cb4fff58/ACEL-23-e14301-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/2da46d70ab3e/ACEL-23-e14301-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/50cabc1040a1/ACEL-23-e14301-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/607557ea49fe/ACEL-23-e14301-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/f7bcecb4ae95/ACEL-23-e14301-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/fdc4cb4fff58/ACEL-23-e14301-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/2da46d70ab3e/ACEL-23-e14301-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/50cabc1040a1/ACEL-23-e14301-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/607557ea49fe/ACEL-23-e14301-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4fc/11561654/f7bcecb4ae95/ACEL-23-e14301-g003.jpg

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本文引用的文献

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SRSF7 downregulation induces cellular senescence through generation of variants.SRSF7 下调通过产生变异体诱导细胞衰老。
Aging (Albany NY). 2023 Dec 29;15(24):14591-14606. doi: 10.18632/aging.205420.
2
The challenge of identifying senescent cells.识别衰老细胞的挑战。
Nat Cell Biol. 2023 Nov;25(11):1554-1556. doi: 10.1038/s41556-023-01267-w.
3
Cell senescence, the senescence-associated secretory phenotype, and cancers.细胞衰老、衰老相关分泌表型与癌症。
PLoS Biol. 2023 Sep 21;21(9):e3002326. doi: 10.1371/journal.pbio.3002326. eCollection 2023 Sep.
4
Splicing factor YBX1 regulates bone marrow stromal cell fate during aging.剪接因子 YBX1 调控衰老过程中骨髓基质细胞的命运。
EMBO J. 2023 May 2;42(9):e111762. doi: 10.15252/embj.2022111762. Epub 2023 Mar 21.
5
Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.ATM、SMG1 和 DDX5 参与 DNA 损伤诱导的可变剪接途径。
Radiat Res. 2023 Apr 1;199(4):406-421. doi: 10.1667/RADE-22-00219.1.
6
Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status.将MDM4作为一种独立于p53状态的前列腺癌新型治疗方法。
Cancers (Basel). 2022 Aug 16;14(16):3947. doi: 10.3390/cancers14163947.
7
CircSCAP interacts with SF3A3 to inhibit the malignance of non-small cell lung cancer by activating p53 signaling.环状 RNA SCAP 与 SF3A3 相互作用，通过激活 p53 信号通路抑制非小细胞肺癌的恶性转化。
J Exp Clin Cancer Res. 2022 Apr 1;41(1):120. doi: 10.1186/s13046-022-02299-0.
8
Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development.衰老细胞为何对凋亡具有抗性：衰老细胞裂解剂开发的见解
Front Cell Dev Biol. 2022 Feb 16;10:822816. doi: 10.3389/fcell.2022.822816. eCollection 2022.
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Aging (Albany NY). 2022 Mar 1;14(5):2081-2100. doi: 10.18632/aging.203924.
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Am J Cancer Res. 2021 Dec 15;11(12):5864-5880. eCollection 2021.