Subramaniam, D. | Search bioRxiv

bioRxiv2021

RNA binding protein RBM3 augments kissing loop formation with lncRNAs to enhance translational control

It is becoming apparent that translational regulation involves the coordinated actions of RNA binding proteins (RBPs) and non-coding RNAs. For efficient translation, mRNA needs to be circularized, which is catalyzed by RNA binding proteins and translation factors. However, the role of lncRNAs in the process is not yet defined. We first performed RNA-seq and RNA- immunoprecipitation coupled-Seq and identified LSAMP-3 and Flii-1. Moreover, modeling studies suggest enhanced kissing loop interactions including of transcripts that encode angiogenesis and epithelial mesenchymal transition. While intestinal epithelial cell specific RBM3 transgenic mice showed increased LSAMP-3 and Flii-1, this was reduced in knockout mice. Also, RBM3 overexpression increased tumor xenograft growth, this was suppressed by knockdown of the lncRNAs. Also, knockdown of endogenous RBM3 reduced lncRNA levels and tumor xenograft growth. In addition, it reduced colitis-associated cancers. We propose that RBPs such as RBM3 mediate their function through regulatory lncRNAs that enable circularization to control translation.

cancer biology↗

bioRxiv2020

Quinomycin A reduces cyst progression in Polycystic Kidney Disease

Polycystic kidney disease (PKD) is a genetic disorder that affects cilia homeostasis and causes progressive growth of tubular-derived cysts within the kidney. Efforts to find safer drugs for PKD have increased in the past few years after the successful launch of tolvaptan, the first approved drug to combat autosomal dominant PKD progression. Here we investigate the effects of Quinomycin A on progression of PKD. Quinomycin A is a bis-intercalator peptide that has previously shown to be effective against cancer progression. Quinomycin A treatment decreased cyst progression of human ADPKD primary renal epithelial cells grown in a 3D collagen gel to form cysts. In an orthologous mouse model of PKD, Quinomycin A administration reduced kidney to body weight ratios, and reduced cystogenesis. This was accompanied by decreased cell proliferation and fibrosis. Quinomycin treatments efficiently reduced the expression of Notch pathway proteins, RBPjk and HeyL in kidneys of PKD mice. Interestingly, Quinomycin treatments also normalized cilia lengths of collecting duct cyst-lining renal epithelia of PKD mice. This is the first preclinical study to our knowledge that demonstrates Quinomycin A has protective effects against PKD progression, in part by reducing Notch signaling and renal epithelial cilia lengths. Our findings suggest Quinomycin A has potential therapeutic value for PKD patients.

genetics↗