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The Fragile X Protein and Genome Function

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Abstract

The fragile X syndrome (FXS) arises from loss of expression or function of the FMR1 gene and is one of the most common monogenic forms of intellectual disability and autism. During the past two decades of FXS research, the fragile X mental retardation protein (FMRP) has been primarily characterized as a cytoplasmic RNA binding protein that facilitates transport of select RNA substrates through neural projections and regulation of translation within synaptic compartments, with the protein products of such mRNAs then modulating cognitive functions. However, the presence of a small fraction of FMRP in the nucleus has long been recognized. Accordingly, recent studies have uncovered several mechanisms or pathways by which FMRP influences nuclear gene expression and genome function. Some of these pathways appear to be independent of the classical role for FMRP as a regulator of translation and point to novel functions, including the possibility that FMRP directly participates in the DNA damage response and in the maintenance of genome stability. In this review, we highlight these advances and discuss how these new findings could contribute to our understanding of FMRP in brain development and function, the neural pathology of fragile X syndrome, and perhaps impact of future therapeutic considerations.

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Acknowledgements

The authors apologize for omission of any relevant works due to space constraints.

Funding

Support from NIH MH108956 and past support from NIH and FRAXA Research Foundation are gratefully acknowledged.

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  1. Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, TN, 37996, USA

    Thomas C. Dockendorff & Mariano Labrador

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  1. Thomas C. Dockendorff
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  2. Mariano Labrador
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Correspondence to Thomas C. Dockendorff or Mariano Labrador.

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Dockendorff, T.C., Labrador, M. The Fragile X Protein and Genome Function. Mol Neurobiol 56, 711–721 (2019). https://doi.org/10.1007/s12035-018-1122-9

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