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Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function.

ABSTRACT: The tumor suppressor BAP1 associates with ASXL1/2 to form the core Polycomb complex PR-DUB, which catalyzes the removal of mono-ubiquitin from several substrates including histone H2A. This complex also mediates the poly-deubiquitination of HCFC1, OGT and PCG1-?, preventing them from proteasomal degradation. Surprisingly, considering its role in a Polycomb complex, no transcriptional signature was consistently found among BAP1-inactivated tumor types. It was hypothesized that BAP1 tumor suppressor activity could reside, at least in part, in stabilizing proteins through its poly-deubiquitinase activity. Quantitative mass spectrometry and gene expression arrays were used to investigate the consequences of BAP1 expression modulation in the NCI-H226 mesothelioma cell line. Analysis of differentially expressed proteins revealed enrichment in cytoskeleton organization, mitochondrial activity and ROS management, while gene expression analysis revealed enrichment in the epithelial-to-mesenchymal transition pathway. Functional assessments in BAP1 inactivated, BAP1 wild-type and BAP1 catalytically dead-expressing NCI-H226 and QR mesothelioma cell lines confirmed alteration of these pathways and demonstrated that BAP1 deubiquitinase activity was mandatory to maintain these phenotypes. Interestingly, monitoring intracellular ROS levels partly restored the morphology and the mitochondrial activity. Finally, the study suggests new tumorigenic and cellular functions of BAP1 and shows for the first time the interest of studying the proteome as readout of BAP1 inactivation.

SUBMITTER: Hebert L

PROVIDER: S-EPMC5641149 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function.

Hebert Lucie L Bellanger Dorine D Guillas Chloé C Campagne Antoine A Dingli Florent F Loew Damarys D Fievet Alice A Jacquemin Virginie V Popova Tatiana T Jean Didier D Mechta-Grigoriou Fatima F Margueron Raphaël R Stern Marc-Henri MH

Oncotarget 20170803 42

The tumor suppressor BAP1 associates with ASXL1/2 to form the core Polycomb complex PR-DUB, which catalyzes the removal of mono-ubiquitin from several substrates including histone H2A. This complex also mediates the poly-deubiquitination of HCFC1, OGT and PCG1-α, preventing them from proteasomal degradation. Surprisingly, considering its role in a Polycomb complex, no transcriptional signature was consistently found among <i>BAP1</i>-inactivated tumor types. It was hypothesized that BAP1 tumor s ...[more]

PMID: 29069806

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Project description:BackgroundLeaf senescence occurs in an age-dependent manner, but the rate and timing of leaf senescence may be influenced by various biotic and abiotic factors. In the course of stress, the function, composition, and different components of photosynthetic apparatus occur to be synthesized homogeneously or degraded paradoxically due to different senescence-related processes. Nitrogen (N) deficiency is one of the critical environmental factors that induce leaf senescence, and its incidence may curtail leaf photosynthetic function and markedly alter the genetic information of plants that might result in low grain yield. However, the physiological and genetic mechanism underlying N deficiency regulates premature senescence, and flag leaf function, ROS homeostasis, and intercellular sugar concentration in rice during grain filling are not well understood. In this paper, Zhehui7954 an excellent indica restorer line (wildtype) and its corresponding mutant (psf) with the premature senescence of flag leaves were used to study the effect of different N supplies in the alteration of physiological and biochemical components of flag leaf organ and its functions during grain filling.ResultsThe results showed that the psf mutant appeared to be more susceptible to the varying N supply levels than WT. For instance, the psf mutant showed considerably lower Pn, Chl a, Chl b, and Car contents than its WT. N deficiency (LN) decreased leaves photosynthetic activities, N metabolites, but significantly burst O2•-, H2O2, and relative conductivity (R1/R2) concentrations, which was consistent with the expression levels of senescence-associated genes. Sucrose, glucose, and C/N ratio concentrations increased with a decrease in N level, which was closely associated with N and non-structural carbohydrate translocation rates. Increases in POD activity were positively linked with the senescence-related enhancement of ROS generation under LN conditions, whereas, SOD, CAT, and APX activities showed opposite trends. High N (HN) supply significantly inhibits the transcripts of carbohydrate biosynthesis genes, while N assimilation gene transcripts gradually increased along with leaf senescence. The psf mutant had a relatively higher grain yield under HN treatment than LN, while WT had a higher grain yield under MN than HN and LN.ConclusionsThis work revealed that the C/N ratio and ROS undergo a gradual increase driven by interlinking positive feedback, providing a physiological framework connecting the participation of sugars and N assimilation in the regulation of leaf senescence. These results could be useful for achieving a higher yield of rice production by appropriate N supply and plant senescence regulation.

Dataset Information

Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function.

Publications

Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function.

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