期刊
MOLECULAR CELL
卷 67, 期 2, 页码 266-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2017.05.027
关键词
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资金
- Associazione Italiana per la Ricerca sul Cancro [IG 16770, IG 15210]
- European Union
- Telethon-Italy [GGP12171]
- Progetti di Ricerca di Interesse Nazionale (PRIN)
- Fondazione Italiana per la Ricerca sul Cancro [18125]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) Fellowship i-Care (Marie Curie - European Union) [16173]
Mec1(ATR) 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 Mec1(ATR) response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.
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