A hydride transfer complex reprograms NAD metabolism and bypasses senescence

Igelmann, Sebastian; Lessard, Frédéric; Uchenunu, Oro; Bouchard, Jacob; Ruiz, Ana Fernández; Rowell, Marie-Camille; Lopes-Paciência, Stéphane; Papadopoli, David; Fouillen, Aurélien; Ponce, Katia Julissa; Huot, Geneviève; Mignacca, Lian; Benfdil, Mehdi; Kalegari, Paloma; Wahba, H.M.; Pěnčík, Jan; Vuong, Nhung; Quenneville, Jordan; Guillon, Jordan; Bourdeau, Véronique; Hulea, Laura; Gagnon, Étienne; Kenner, Lukas; Moriggl, Richard; Nanci, Antonio; Pollak, Michael; Omichinski, James G.; Topisirović, Ivan; Ferbeyre, Gerardo

doi:10.1016/j.molcel.2021.08.028

Cited by 30 publications

(28 citation statements)

References 76 publications

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“…Immunofluorescence were done as described ( Igelmann et al, 2021 ) with the following modifications for the AGO1x staining. For blocking 10% goat serum (#16210072, Life Technologies), and 1% BSA (BioShop Canada) in PBS for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…Senescent and non-senescent IMR-90 s were collected at 12- or 35-days post-infection, with either pBabe-H-RasV12 or pBabe control vector in TRIzol reagent (Invitrogen) and total RNA was extracted following manufacturer's instructions. Two μg of total RNA were then used for the RT-qPCR reactions as described in ( Igelmann et al, 2021 ). Primers for qPCR were designed using the Universal Probe Library Assay Design Center ( ) and are provided in .…”

Section: Methodsmentioning

confidence: 99%

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Cellular senescence limits translational readthrough

et al. 2021

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The origin and evolution of cancer cells is considered to be mainly fueled by DNA mutations. Although translation errors could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called caretakers block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretakers genes should prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the process of cellular senescence induced by oncogenes, tumor suppressors or chemotherapeutic drugs is associated to a reduction in translational readthrough (TR) measured using reporters containing termination codons withing the context of both normal translation termination or programmed TR. Senescence reduced both basal TR and TR stimulated by aminoglycosides. Mechanistically, the reduction of TR during senescence is controlled by the RB tumor suppressor pathway. Cells that escape from cellular senescence either induced by oncogenes or chemotherapy have an increased TR. Also, breast cancer cells that escape from therapy-induced senescence express high levels of AGO1x, a TR isoform of AGO1 linked to breast cancer progression. We propose that senescence and the RB pathway reduce TR limiting proteome diversity and the expression of TR proteins required for cancer cell proliferation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cellular senescence limits translational readthrough

et al. 2021

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“…Damage to membranes can be overcome by several different repair systems [19]. Although protein, membrane and other repair systems [20] are highly effective, they are not infallible, at least in the somatic cells of animals. DCC accumulate as time goes on, sooner or later resulting in cellular senescence [21][22][23].…”

Section: The Repair Of Cellular Damagementioning

confidence: 99%

Cellular senescence, rejuvenation and potential immortality

Sheldrake

2022

Proc. R. Soc. B.

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Ageing, death, and potential immortality lie at the heart of biology, but two seemingly incompatible paradigms coexist in different research communities and have done since the nineteenth century. The universal senescence paradigm sees senescence as inevitable in all cells. Damage accumulates. The potential immortality paradigm sees some cells as potentially immortal, especially unicellular organisms, germ cells and cancerous cells. Recent research with animal cells, yeasts and bacteria show that damaged cell constituents do in fact build up, but can be diluted by growth and cell division, especially by asymmetric cell division. By contrast, mammalian embryonic stem cells and many cancerous and ‘immortalized’ cell lines divide symmetrically, and yet replicate indefinitely. How do they acquire their potential immortality? I suggest they are rejuvenated by excreting damaged cell constituents in extracellular vesicles. If so, our understanding of cellular senescence, rejuvenation and potential immortality could be brought together in a new synthesis, which I call the cellular rejuvenation hypothesis: damaged cell constituents build up in all cells, but cells can be rejuvenated either by growth and cell division or, in ‘immortal’ cell lines, by excreting damaged cell constituents. In electronic supplementary material, appendix, I outline nine ways in which this hypothesis could be tested.

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“…Mitochondrial dysfunction causes a decreased NAD + /NADH ratio and increased reactive oxygen species (ROS), resulting in senescence (Wiley and Campisi, 2016). STAT3 deficiency induces senescence, mitochondrial dysfunction, and a lower NAD + /NADH ratio (Igelmann et al, 2021). The dynamic changes of NAD + /NADH ratio also has an effect on nonhistone deacetylation of lysine residues of sirtuins.…”

Section: Nicotinamide Adenine Dinucleotide (Nad + )mentioning

confidence: 99%

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

Huo

Zhang

Huang

et al. 2021

Front. Cell Dev. Biol.

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Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

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A hydride transfer complex reprograms NAD metabolism and bypasses senescence

Cited by 30 publications

References 76 publications

Cellular senescence limits translational readthrough

Cellular senescence limits translational readthrough

Cellular senescence, rejuvenation and potential immortality

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

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