FMRP safeguards long mRNA expression by opposing repressive RNP states
- 1The University of British Columbia
Abstract
Fragile X messenger ribonucleoprotein (FMRP) is widely viewed as a translational repressor, yet its loss paradoxically compromises expression of exceptionally long, dosage-sensitive neurodevelopmental mRNAs. First shown in Drosophila oocytes, this selective loss extends to mouse cortex and hippocampus, but its mechanism remains unknown. Here, we uncover a protective function for FMRP: shielding long mRNAs from repression by Me31B/DDX6, a conserved RNA helicase that organizes repressive RNP complexes. In Drosophila oocytes, FMRP loss redirects target mRNAs into Me31B-marked P-bodies. Transcriptome-wide binding maps reveal extensive FMRP-Me31B co-occupancy, preferentially concentrated on long coding sequences whose translation depends on FMRP. Strikingly, disrupting Me31B-dependent repression preferentially enhances translation of FMRP targets in FMRP-deficient oocytes. We identify Rin/G3BP, Caprin, and Lig/UBAP2L as FMRP-associated cofactors supporting expression of distinct targets. Together, our findings challenge the prevailing view of FMRP as a translational repressor, revealing instead a mechanism that safeguards vulnerable neurodevelopmental mRNAs from inappropriate cytoplasmic silencing.
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BibTeX
@misc{ma2026fmrp,
title = {{FMRP safeguards long mRNA expression by opposing repressive RNP states}},
author = {K. Ma and A. R. Hossain and K. L. Judson and T. Q. Cheng and E. J. Greenblatt},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.23.739932},
url = {https://www.biorxiv.org/content/10.64898/2026.07.23.739932v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - FMRP safeguards long mRNA expression by opposing repressive RNP states
AU - K. Ma
AU - A. R. Hossain
AU - K. L. Judson
AU - T. Q. Cheng
AU - E. J. Greenblatt
PY - 2026
DA - 2026/07/23
PB - bioRxiv
DO - 10.64898/2026.07.23.739932
UR - https://www.biorxiv.org/content/10.64898/2026.07.23.739932v2
AB - Fragile X messenger ribonucleoprotein (FMRP) is widely viewed as a translational repressor, yet its loss paradoxically compromises expression of exceptionally long, dosage-sensitive neurodevelopmental mRNAs. First shown in Drosophila oocytes, this selective loss extends to mouse cortex and hippocampus, but its mechanism remains unknown. Here, we uncover a protective function for FMRP: shielding long mRNAs from repression by Me31B/DDX6, a conserved RNA helicase that organizes repressive RNP complexes. In Drosophila oocytes, FMRP loss redirects target mRNAs into Me31B-marked P-bodies. Transcriptome-wide binding maps reveal extensive FMRP-Me31B co-occupancy, preferentially concentrated on long coding sequences whose translation depends on FMRP. Strikingly, disrupting Me31B-dependent repression preferentially enhances translation of FMRP targets in FMRP-deficient oocytes. We identify Rin/G3BP, Caprin, and Lig/UBAP2L as FMRP-associated cofactors supporting expression of distinct targets. Together, our findings challenge the prevailing view of FMRP as a translational repressor, revealing instead a mechanism that safeguards vulnerable neurodevelopmental mRNAs from inappropriate cytoplasmic silencing.
ER -