The maintenance of genome stability is essential for the cell as the integrity of genomic information guaranties reproduction of a whole organism. DNA damage occurring in response to different ...natural and nonnatural stimuli (errors in DNA replication, UV radiation, chemical agents, etc.) is normally detected by special cellular machinery that induces DNA repair. However, further accumulation of genetic lesions drives the activation of cell death to eliminate cells with defective genome. This particular feature is used for targeting fast-proliferating tumor cells during chemo-, radio-, and immunotherapy. Among different cell death modalities induced by DNA damage, apoptosis is the best studied. Nevertheless, nonapoptotic cell death and adaptive stress responses are also activated following genotoxic stress and play a crucial role in the outcome of anticancer therapy. Here, we provide an overview of nonapoptotic cell death pathways induced by DNA damage and discuss their interplay with cellular senescence, mitotic catastrophe, and autophagy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Necroptosis as a Novel Facet of Mitotic Catastrophe Egorshina, Aleksandra Yu; Zamaraev, Alexey V; Kaminskyy, Vitaliy O ...
International journal of molecular sciences,
03/2022, Volume:
23, Issue:
7
Journal Article
Peer reviewed
Open access
Mitotic catastrophe is a defensive mechanism that promotes elimination of cells with aberrant mitosis by triggering the cell-death pathways and/or cellular senescence. Nowadays, it is known that ...apoptosis, autophagic cell death, and necrosis could be consequences of mitotic catastrophe. Here, we demonstrate the ability of a DNA-damaging agent, doxorubicin, at 600 nM concentration to stimulate mitotic catastrophe. We observe that the inhibition of caspase activity leads to accumulation of cells with mitotic catastrophe hallmarks in which RIP1-dependent necroptotic cell death is triggered. The suppression of autophagy by a chemical inhibitor or
knockout upregulates RIP1 phosphorylation and promotes necroptotic cell death. Thus, in certain conditions mitotic catastrophe, in addition to apoptosis and autophagy, can precede necroptosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Caspase-2 is a unique and conservative cysteine protease which plays an important role in several cellular processes including apoptotic cell death. Although the molecular mechanisms of its ...activation remain largely unclear, a major role belongs to the architecture of the caspase-2 active center. We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity. Strikingly, in silico analysis using molecular dynamics simulations has shown that Serine-384 is crucially involved in interactions within the caspase-2 active center. It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate. Hence, Serine-384 is essential for supporting a proper architecture of the active center of caspase-2. Moreover, molecular modeling strongly proved steric inaccessibility of Ser-384 to be phosphorylated. Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity. Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2. Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma. Taken together, we have uncovered a central feature of the caspase-2 activation mechanism which is crucial for the regulation of its signaling network.
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