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

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.