Loss of the fragile X syndrome protein FMRP results in misregulation of nonsense-mediated mRNA decay.

ABSTRACT: Loss of the fragile X protein FMRP is a leading cause of intellectual disability and autism^1,2, but the underlying mechanism remains poorly understood. We report that FMRP deficiency results in hyperactivated nonsense-mediated mRNA decay (NMD)^3,4 in human SH-SY5Y neuroblastoma cells and fragile X syndrome (FXS) fibroblast-derived induced pluripotent stem cells (iPSCs). We examined the underlying mechanism and found that the key NMD factor UPF1 binds directly to FMRP, promoting FMRP binding to NMD targets. Our data indicate that FMRP acts as an NMD repressor. In the absence of FMRP, NMD targets are relieved from FMRP-mediated translational repression so that their half-lives are decreased and, for those NMD targets encoding NMD factors, increased translation produces a

SUBMITTER: Kurosaki T 

PROVIDER: S-EPMC8273690 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature