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

Abstract

SummaryMec1ATR 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.

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

“…Through institution of several mechanisms, including base excision repair, nucleotide excision repair, mismatch repair (MMR), homologous recombination, and nonhomologous end joining, a robust DNA damage response (DDR) is established in different stages of the cell cycle to repair any DNA damage . Interestingly, DDR is activated through the inhibition of PP2A …”

“…379 Interestingly, DDR is activated through the inhibition of PP2A. 380 Somatic point mutation can conceivably occur due to the failure in base excision repair, nucleotide excision repair, or MMR. In endometriosis, however, only the aspect of MMR has been investigated so far, mostly in the context of potential for malignant transformation.…”

Beyond Computational Genomics towards Systems Metabolomics for Precision Oncology

“…5C), in which DNA damage response (DDR), mismatch repair, aneuploidy and similar processes play a role, increasing the mutation load of developing tumors (69). Given that trajectories of mutations appear to follow detectable patterns (70,71,72) and that nutrient-sensing and metabolic pathways have been reported to interfere with DDR (73), also this biological process may open new ways to drug discovery.…”

PP2A Regulates Phosphorylation-Dependent Isomerization of Cytoplasmic and Mitochondrial-Associated ATR by Pin1 in DNA Damage Responses

“…Protein phosphatase 2A (PP2A) plays an important role in regulating DNA damage responses (DDR) by dephosphorylating DDR proteins to change the phosphorylation status of proteins that are critical to genome stability ( Freeman and Monteiro, 2010 ; Harris and Bunz, 2010 ; Palii et al, 2013 ; Ferrari et al, 2017 ; Merigliano et al, 2017 ; Ramos et al, 2019 ). Substrates of PP2A in DDR include ATR, ATM, DNA-PK, Chk1, Chk2, p53, and so on ( Ramos et al, 2019 ).…”

“…All these regulations are carried out in the nucleus where DNA damage checkpoint signaling occurs. For example, PP2A activation attenuates ATR/ATR-dependent DDR ( Ferrari et al, 2017 ). Inhibition or knockdown of PP2A leads to an increase of y-H2AX, an important DNA damage signal of DNA strand breaks ( Nazarov et al, 2003 ; Chowdhury et al, 2005 ; Keogh et al, 2006 ).…”