FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation

Significance This study shows that Fragile X mental retardation protein (FMRP) promotes messenger RNA (mRNA)-dependent recombination via facilitating ten-eleven translocation protein 1 (TET1)-mediated mRNA methyl-5-cytosine (m5C) demethylation. Loss of FMRP leads to damage induced mRNA m5C and R-loop accumulation at sites of active transcription, defective recombination repair, and increased radiosensitivity of tumor cells. FMRP-dependent RNA m5C demethylation and R-loop resolving during DNA repair are important for repair completion and the maintenance of genome stability. The removal of m5C by the FMRP–TET1 axis is coupled with R-loop dissolution, which ensures proper completion of DNA repair and survival of cells after DNA damage. These findings significantly advance our understanding of the regulation of RNA modifications in R-loop dynamics during DNA repair.