Poster abstracts
Poster number 87 submitted by MaKenzie Scarpitti
FMRP inhibits translation elongation independent of G-quadruplexes
MaKenzie R. Scarpitti (The Biomedical Sciences Graduate Program, Department of Biological Chemistry and Pharmacology, Center for RNA Biology, The Ohio State University), Michael G. Kearse (The Biomedical Sciences Graduate Program, Department of Biological Chemistry and Pharmacology, Center for RNA Biology, The Ohio State University)
Abstract:
Loss of expression of fragile X mental retardation protein (FMRP) causes fragile X syndrome, the leading form of inherited intellectual disability and the most common monogenic cause of autism spectrum disorders. FMRP is an RNA-binding protein that controls neuronal mRNA localization and translation. How FMRP controls translation remains largely unclear but it may use multiple mechanisms to target different steps of translation. Most notably, FMRP is thought to inhibit translation elongation on target transcripts that contain RNA G-quadruplex (G4) structures within the coding sequence. Here we directly test this model and report that FMRP inhibits translation elongation independent of G4s in the mRNA coding sequence. Furthermore, we define that the RGG box motif together with its natural C-terminal domain forms a non-canonical RNA-binding domain (ncRBD) that enables FMRP to bind mRNA independently of sequence or structure. Only when FMRP is bound to mRNA through this ncRBD does FMRP inhibit translation. Furthermore, the ncRBD of FMRP stalls elongating ribosomes on transcripts and thereby promotes accumulation of heavy polysomes. Together, this work shifts our understanding of how FMRP represses translation elongation and supports a model where repression is driven by local FMRP concentration rather than mRNA sequence.
Keywords: RNA binding protein, mRNA, ribosomes