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:
拼接机器中的缺陷与各种疾病有关,包括癌症.我们观察到人类细胞系中剪接体成分和剪接调节因子的表达普遍减少,应激诱导,端粒脱帽诱导衰老。支持有缺陷的拼接有助于衰老的观点,剪接抑制剂herboxidiene,在正常和癌细胞系中,和帕二烯醇内酯B诱导衰老。此外,消耗单个剪接体成分也促进衰老。所有衰老类型都与从MDM4-FL变体到MDM4-S的选择性剪接转换相关。当剪接被抑制时,MDM4剪接移位被再现,剪接体组件被耗尽。虽然降低内源性MDM4的水平促进衰老和细胞存活,但与MDM4-S表达状态无关,增加MDM4-S也改善了细胞存活率。总的来说,我们的工作确定剪接缺陷调节MDM4的选择性剪接以促进衰老和细胞存活。