AI Article Synopsis

  • * The process of MOID is influenced by the release of mitochondrial AIFM1 mediated by proteins PML and DAXX, indicating a complex interplay between mitochondrial function and cell survival mechanisms.
  • * Both MAD2 and TSG101 interact at PML nuclear bodies during interphase, and specific phosphorylation states of TSG101 are essential for this localization, emphasizing a vital regulatory pathway in controlling cell death and survival in cancer contexts.

Article Abstract

Overexpression of mitotic arrest deficiency 2 (MAD2/MAD2L1), a pivotal component of the spindle assembly checkpoint (SAC), resulted in many types of cancer. Here we show that the depletion of tumor susceptibility gene 101 (TSG101), causes synthetic dosage lethality (SDL) in MAD2-overexpressing cells, and we term this cell death MAD2-overexpressing interphase cell death (MOID). The induction of MOID depends on PML and DAXX mediating mitochondrial AIFM1-release. MAD2, TSG101, and AIF-PML-DAXX axis regulate mitochondria, PML nuclear bodies (NBs), and autophagy with close inter-dependent protein stability in survival cells. Loss of C-terminal phosphorylation(s) of TSG101 and closed (C-)MAD2-overexpression contribute to induce MOID. In survival cells, both MAD2 and TSG101 localize at PML NBs in interphase, and TSG101 Y390 phosphorylation is required for localization of TSG101 to PML NBs. PML release from PML NBs through PML deSUMOylation contributes to induce MOID. The post-transcriptional/translational cell death machinery and the non-canonical transcriptional regulation are intricately linked to MOID, and ER-MAM, may serve as a crucial intersection for MOID signaling.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11570632PMC
http://dx.doi.org/10.1038/s41419-024-07229-wDOI Listing

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