Homologous recombination

Gene

Cell biology

Linguistics

Philosophy

Molecular biology

Biology

Messenger RNA

Transcription (linguistics)

Demethylation

DNA demethylation

DNA methylation

Genetics

DNA repair

Chemistry

Gene expression

Proceedings of the National Academy of Sciences

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.

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