Description:

Speaker: Lynne E. Maquat, PhD; Professor, Departments of Biochemistry & Biophysics, Oncology, and Pediatrics; School of Medicine and Dentistry; Director, Center for RNA Biology: From Genome to; Therapeutics; University of Rochester. 

LECTURE TITLE: Nonsense-mediated mRNA decay in human and disease: Reframing the role of FMRP in Fragile X Syndrome. 

LECTURE ABSTRACT: Much progress has been made on how nonsense-mediated mRNA decay (NMD), which we first described for humans in 1981, controls the quality of gene expression by detecting and rapidly degrading aberrant mRNAs that harbor a premature termination codon. NMD also degrades ~5−10% physiological mRNAs that are key to the maintenance of cellular homeostasis in a changing environmental milieu. And, NMD can be misregulated in diseases, as we have serendipitously found for Fragile X Syndrome (FXS) – a leading single-gene cause of intellectual disability and autism due to a deficiency in the RNA-binding protein Fragile X Protein (FMRP). NMD is hyperactivated in FXS patient-derived cells and a mouse model of FXS. Our foray into FXS and FMRP function has led us to examine the mechanism by which FMRP regulates its ~6000 mRNA targets, one-third of which are NMD targets. We have found that, as a rule, FMRP-binding to a target mRNA results in its translational repression and protection from decay. 

While FMRP-mediated translational repression has been attributed primarily to ribosome stalling, we have found using immunoprecipitations and polysome profiling of nonpolar- and polar-cell lysates, and LC-MS/MS analyses, that FMRP largely represses translation initiation by associating with granule constituents to preclude 40S ribosomal subunit binding. We demonstrate that FMRP associates with its target mRNAs by binding directly to eIF4E at the 5'-cap in competition with eIF4G1, and that the granule constituent Ataxin-2-Like promotes FMRP binding to the transcribed body. The KH1+KH2 domains of FMRP are critical for its co-immunoprecipitation of eIF4E, mRNA targets, Ataxin-2-Like and the poly(A)-binding protein PABPC1.