Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response.
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ABSTRACT:
SUBMITTER: McMahon KA
PROVIDER: S-EPMC8279762 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Caveolae-associated protein 3 (cavin3), a putative tumor suppressor protein, is inactivated in most cancers. The molecular basis for its actions remains poorly understood. We characterized the effects on the proteome of cavin3 loss by utilizing genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair pathways with downregulation of BRCA1 and the BRCA1 A-complex components. Using cellular and cell-free expression assays, we show a direct interaction between BRCA1 and cavin3. Association of BRCA1 and cavin3 occurs when cavin3 is released from disassembling caveolae by multiple stressors such as UV and mechanical stress. Cavin3-deficient cells were sensitised to PARP inhibition and showed a loss of components of the BRCA1 A-complex associated with UV DNA damage foci. Overexpression and RNAi-depletion strategies in several cancer cell lines revealed that cavin3 sensitized a variety of cancer cells to UV-induced apoptosis. We conclude that cavin3 functions together with BRCA1 in multiple pathways that contribute to tumorigenesis.
2021-06-15 | PXD026724 | Pride
Project description:Caveolae are an abundant and characteristic surface feature of many vertebrate cells. The uniform shape of caveolae is characterized by a bulb with consistent curvature connected to the plasma membrane (PM) by a neck region with opposing curvature. Caveolae act in mechanoprotection by flattening in response to increased membrane tension, and their disassembly influences the lipid organization of the PM. Here, we review evidence for caveolae as a specialized lipid domain and speculate on mechanisms that link changes in caveolar shape and/or protein composition to alterations in specific lipid species. We propose that high membrane curvature in specific regions of caveolae can enrich specific lipid species, with consequent changes in their localization upon caveolar flattening. In addition, we suggest how changes in the association of lipid-binding caveolar proteins upon flattening of caveolae could allow release of specific lipids into the bulk PM. We speculate that the caveolae-lipid system has evolved to function as a general stress-sensing and stress-protective membrane domain.
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Project description:Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
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