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Título

PP2A controls genome integrity by integrating nutrient-sensing and metabolic pathways with the DNA damage response

AutorFerrari, Elisa; Bermejo, Rodrigo; Foiani, Marco
Palabras claveDNA damage response
Mec1-ATR
Protein phosphatase PP2A
TORC1
Metabolism
Genome stability
Rad53
Irc21
Fecha de publicación20-jul-2017
EditorElsevier
CitaciónMolecular Cell 67, 266–281 (2017)
ResumenMec1ATR mediates 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 Mec1ATR response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.
Descripción21 p.-7 fig. Ferrari, Elisa et al.
Versión del editorhttp://dx.doi.org/10.1016/j.molcel.2017.05.027
URIhttp://hdl.handle.net/10261/154055
DOI10.1016/j.molcel.2017.05.027
ISSN1097-2765
E-ISSN1097-4164
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