Abstract
Caveolae-associated protein 3 (cavin3) is inactivated in most cancers. We characterized how cavin3 affects the cellular proteome using genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair, with BRCA1 and BRCA1 A-complex components being downregulated on cavin3 deletion. Cellular and cell-free expression assays revealed a direct interaction between BRCA1 and cavin3 that occurs when cavin3 is released from caveolae that are disassembled in response to UV and mechanical stress. Overexpression and RNAi-depletion revealed that cavin3 sensitized various cancer cells to UV-induced apoptosis. Supporting a role in DNA repair, cavin3-deficient cells were sensitive to PARP inhibition, where concomitant depletion of 53BP1 restored BRCA1-dependent sensitivity to PARP inhibition. We conclude that cavin3 functions together with BRCA1 in multiple cancer-related pathways. The loss of cavin3 function may provide tumor cell survival by attenuating apoptotic sensitivity and hindering DNA repair under chronic stress conditions.
Highlights
Caveolae are an abundant surface feature of most vertebrate cells
Their levels were restored by the expression of exogenous cavin3, confirming the specificity of the KO effect (Figure 1—figure supplement 1C)
We further evaluated several other proteins: chromodomain helicase DNA-containing protein 3 (CHD3, an epigenetic modulator) and Fanconi anemia (FA) complementation Group 2 (FANCD2, a DNA damage sensor protein) that were upregulated in cavin3 KO cells and that are involved in different aspects of DNA repair
Summary
Caveolae are 50–100 nm bulb-shaped structures attached to the plasma membrane (Parton and del Pozo, 2013). One of the defining features of this domain is the integral membrane protein caveolin-1 (CAV1). CAV1 is a structural component of caveolae regulating diverse cellular processes, including endocytosis, vesicular transport, cell migration, and signal transduction (Parton and del Pozo, 2013). We and others have characterized a caveolar adaptor molecule, caveolae-associated protein 3 (cavin3) (McMahon et al, 2009). Cavin belongs to a family of proteins that includes caveolae-associated protein 1 (cavin1), caveolae-associated protein 2 (cavin2), and the muscle-specific member caveolae-associated protein 4 (cavin4) (Ariotti and Parton, 2013; Bastiani et al, 2009; Hansen et al, 2009; Kovtun et al, 2015; Lo et al, 2015; McMahon et al, 2009).
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