MAD2-overexpressing interphase cell death (MOID)

An in-depth comprehension of the molecular mechanisms behind the targeted eradication of cancer cells through cell death represents a requisite for effective anticancer treatments. However, the precise mechanism by which cell divisionrelated factors interact with intracellular organelles in the context of cancer cell death remains unclear. Mitotic arrest deficiency 2 (MAD2/MAD2L1), a pivotal component of the spindle assembly checkpoint (SAC), and its overexpression also resulted in many types of cancer. Here we show that the depletion of a microtubule-binding protein, 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). MOID induction is p53-independent but AIFM1-dependent and caspase-activated cell death. The induction of MOID depends on PML and DAXX mediating mitochondrial AIFM1-release. C-terminal phosphorylations of TSG101 and closed (C-)MAD2-overexpression are required to induce MOID. Additionally, a part of MAD2 colocalizes with PML at PML nuclear bodies (PML NBs), and the PML release from PML NBs through PML deSUMOylation is required to induce MOID. The post-transcriptional/translational cell death machinery and the non-canonical transcriptional regulation of oxidative stress and ATM/ATR-mediated DNA double-strand breaks (DSB) - DNA damage response (DDR) are intricately linked to MOID. MOID is also associated with the activation of ROS and autophagy. PML localized at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), i.e., ER-MAM, may serve as a crucial intersection for MOID signaling.