Mec1ATRmediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATRresponse. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.

PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response / E. Ferrari, C. Bruhn, M. Peretti, C. Cassani, W. Carotenuto, M. Elgendy, G. Shubassi, C. Lucca, R. Bermejo, M. Varasi, S. Minucci, M.P. Longhese, M. Foiani. - In: MOLECULAR CELL. - ISSN 1097-2765. - 67:2(2017 Jul 20), pp. 266-281.e4. [10.1016/j.molcel.2017.05.027]

PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response

E. Ferrari
Primo
;
M. Peretti;W. Carotenuto;S. Minucci;M. Foiani
Ultimo
2017-07-20

Abstract

Mec1ATRmediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATRresponse. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.
DNA damage response; genome stability; Irc21; Mec1-ATR; metabolism; protein phosphatase PP2A; Rad53; TORC1; Adaptor Proteins, Signal Transducing; Ceramides; Cytochrome-B(5) Reductase; DNA, Fungal; Enzyme Activation; Gene Expression Regulation, Fungal; Intracellular Signaling Peptides and Proteins; Metabolomics; Mutation; Protein Kinase Inhibitors; Protein Methyltransferases; Protein Phosphatase 2; Protein-Serine-Threonine Kinases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sirolimus; Transcription Factors; DNA Damage; DNA Repair; Energy Metabolism; Genome, Fungal; Genomic Instability; Molecular Biology; Cell Biology
Settore BIO/11 - Biologia Molecolare
ATR and ATM-mediated control of chromosome integrity and cell plasticity
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/562096
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