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Fragile X syndrome, the most common form of inherited mental retardation, is caused by the loss of the fragile X mental retardation protein (FMRP). FMRP is a ubiquitously expressed, multi-domain RNA-binding protein, but its  in vivo  function remains poorly understood. Recent studies have shown that FMRP participates in cell cycle control during development. Here, we used  Drosophila  mutants to test if FMRP plays a role in DNA damage response under genotoxic stress. We found significantly fewer  dfmr1  mutants survived to adulthood than wild-types following irradiation or exposure to chemical mutagens, demonstrating that the loss of drosophila FMRP (dFMRP) results in hypersensitivity to genotoxic stress. Genotoxic stress significantly reduced mitotic cells in wild-type brains, indicating the activation of a DNA damage-induced G2/M checkpoint, while mitosis was only moderately suppressed in  dfmr1  mutants. Elevated expression of cyclin B, a protein critical for the G2 to M transition, was observed in the larval brains of  dfmr1  mutants.  CycB  mRNA transcripts were enriched in the dFMRP-containing complex, suggesting that dFMRP regulates DNA damage-induced G2/M checkpoint by repressing  CycB  mRNA translation. Reducing  CycB  dose by half in  dfmr1  mutants rescued the defective G2/M checkpoint and reversed hypersensitivity to genotoxic stress. In addition,  dfmr1  mutants exhibited more DNA breaks and elevated p53-dependent apoptosis following irradiation. Moreover, a loss-of-heterozygosity assay showed decreased irradiation-induced genome stability in  dfmr1  mutants. Thus, dFMRP maintains genome stability under genotoxic stress and regulates the G2/M DNA damage checkpoint by suppressing CycB expression.

Drosophila FMRP participates in the DNA damage response by regulating G2/M cell cycle checkpoint and apoptosis