TY - JOUR
T1 - PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response
AU - Ferrari, Elisa
AU - Bruhn, Christopher
AU - Peretti, Marta
AU - Cassani, Corinne
AU - Carotenuto, Walter Vincenzo
AU - Elgendy, Mohamed
AU - Shubassi, Ghadeer
AU - Lucca, Chiara
AU - Bermejo, Rodrigo
AU - Varasi, Mario
AU - Minucci, Saverio
AU - Longhese, Maria Pia
AU - Foiani, Marco
PY - 2017/7/20
Y1 - 2017/7/20
N2 - 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.
AB - 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.
KW - DNA damage response
KW - genome stability
KW - Irc21
KW - Mec1-ATR
KW - metabolism
KW - protein phosphatase PP2A
KW - Rad53
KW - TORC1
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UR - http://www.scopus.com/inward/citedby.url?scp=85021060845&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2017.05.027
DO - 10.1016/j.molcel.2017.05.027
M3 - Article
C2 - 28648781
AN - SCOPUS:85021060845
VL - 67
SP - 266-281.e4
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -