BC1-FMRP interaction is modulated by 2’-O Methylation: RNA-binding activity of the Tudor domain and translational regulation at synapses

The Brain Cytoplasmic RNA, BC1, is a small non-coding RNA that is found in different RNP particles, some of which are involved in translational control. One component of BC1-containing RNP complexes is the Fragile X Mental Retardation Protein (FMRP) that is implicated in translational repression. Peptide mapping and computational simulations show that the Tudor domain of FMRP makes specific contacts to BC1 RNA. Endogenous BC1 RNA is 2’-O-methylated in nucleotides that contact the FMRP interface, and methylation can affect this interaction. BC1 2’-O-methylations are present in both the nucleus and the cytoplasm of the cell body, but virtually absent at synapses where the FMRP-BC1-mRNA complex exerts its function. Finally, we show that BC1 RNA regulates translation of some FMRP mRNA targets at synapses. In conclusion, these results strongly suggest that subcellular region-specific modifications of BC1 affect the binding to FMRP and therefore translational regulation by the FMRP-BC1 complex.