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The nuclear isoforms of the Fragile X mental retardation RNA-binding protein associate with genomic DNA bridges.

ABSTRACT: The fragile-X mental retardation protein (FMRP) is a canonical RNA-binding protein whose absence in humans leads to the development of the fragile-X syndrome, characterized by multiple phenotypes including neurodevelopmental disorders, intellectual disability, autism, and macroorchidism. The primary transcripts of the FMR1 gene undergo extensive alternative splicing processes, and multiple protein isoforms are produced. The predominantly cytoplasmic isoforms are translational regulators, while the roles of the nuclear ones have been neglected. In this study, we discovered that nuclear FMRP isoforms specifically associate with DNA bridges, aberrant genomic structures that form during mitosis and whose accumulation can drive genome instability by inducing DNA damage. Further localization studies showed that a subset of FMRP-positive bridges contain proteins that have been shown to associate with specific DNA bridges known as ultrafine DNA bridges (UFBs) and surprisingly are RNA positive. Significantly, the depletion of nuclear FMRP isoforms promotes the accumulation of DNA bridges, correlating with the accumulation of DNA damages and cell death, unveiling an important function of these neglected isoforms.

SUBMITTER: Ledoux N

PROVIDER: S-EPMC10162414 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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The nuclear isoforms of the Fragile X mental retardation RNA-binding protein associate with genomic DNA bridges.

Ledoux N N Gauthier-Naud W W Lavoie O O Watters V V Hussein S S Adjibade P P Mazroui R R

Molecular biology of the cell 20230308 5

The fragile-X mental retardation protein (FMRP) is a canonical RNA-binding protein whose absence in humans leads to the development of the fragile-X syndrome, characterized by multiple phenotypes including neurodevelopmental disorders, intellectual disability, autism, and macroorchidism. The primary transcripts of the <i>FMR1</i> gene undergo extensive alternative splicing processes, and multiple protein isoforms are produced. The predominantly cytoplasmic isoforms are translational regulators, ...[more]

PMID: 36884289

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Project description:Fragile X mental retardation protein is an mRNA-binding protein associated with phenotypic manifestations of fragile X syndrome, an X-linked disorder caused by mutation in the FMR1 gene that is the most common inherited cause of intellectual disability. Despite the well-studied genetic mechanism of the disease, the proteoforms of fragile X mental retardation protein have not been thoroughly characterized. Here, we report the expression and mass spectrometric characterization of human fragile X mental retardation protein. FMR1 cDNA clone was transfected into human HEK293 cells to express the full-length human fragile X mental retardation protein. Purified fragile X mental retardation protein was subjected to trypsin digestion and characterized by mass spectrometry. Results show 80.5% protein sequence coverage of fragile X mental retardation protein (Q06787, FMR1_HUMAN) including both the N- and C-terminal peptides, indicating successful expression of the full-length protein. Identified post-translational modifications include N-terminal acetylation, phosphorylation (Ser600), and methylation (Arg290, 471, and 474). In addition to the full-length fragile X mental retardation protein isoform (isoform 6), two endogenous fragile X mental retardation protein alternative splicing isoforms (isoforms 4 and 7), as well as fragile X mental retardation protein interacting proteins, were also identified in the co-purified samples, suggesting the interaction network of the human fragile X mental retardation protein. Quantification was performed at the peptide level, and this information provides important reference for the future development of a targeted assay for quantifying fragile X mental retardation protein in clinical samples. Collectively, this study provides the first comprehensive report of human fragile X mental retardation protein proteoforms and may help advance the mechanistic understanding of fragile X syndrome and related phenotypes associated with the FMR1 mutation.

Dataset Information

The nuclear isoforms of the Fragile X mental retardation RNA-binding protein associate with genomic DNA bridges.

Publications

The nuclear isoforms of the Fragile X mental retardation RNA-binding protein associate with genomic DNA bridges.

Similar Datasets

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