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

Elisa Ferrari, Christopher Bruhn, Marta Peretti, Corinne Cassani, Walter Vincenzo Carotenuto, Mohamed Elgendy, Ghadeer Shubassi, Chiara Lucca, Rodrigo Bermejo, Mario Varasi, Saverio Minucci, Maria Pia Longhese, Marco Foiani

Research output: Contribution to journalArticlepeer-review

Abstract

Mec1ATR 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.

Original languageEnglish
Pages (from-to)266-281.e4
JournalMolecular Cell
Volume67
Issue number2
DOIs
Publication statusPublished - Jul 20 2017

Keywords

  • DNA damage response
  • genome stability
  • Irc21
  • Mec1-ATR
  • metabolism
  • protein phosphatase PP2A
  • Rad53
  • TORC1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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