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

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Abstract

RNA modifications regulate a variety of cellular processes including DNA repair. The RNA methyltransferase TRDMT1 generates methyl-5-cytosine (m5C) on messenger RNA (mRNA) at DNA double-strand breaks (DSBs) in transcribed regions, promoting transcription-coupled homologous recombination (HR). Here, we identified that Fragile X mental retardation protein (FMRP) promotes transcription-coupled HR via its interaction with both the m5C writer TRDMT1 and the m5C eraser ten-eleven translocation protein 1 (TET1). TRDMT1, FMRP, and TET1 function in a temporal order at the transcriptionally active sites of DSBs. FMRP displays a higher affinity for DNA:RNA hybrids containing m5C-modified RNA than for hybrids without modification and facilitates demethylation of m5C by TET1 in vitro. Loss of either the chromatin-@@@@@or RNA-binding domain of FMRP compromises demethylation of damage-induced m5C in cells. Importantly, FMRP is required for R-loop resolving in cells. Due to unresolved R-loop and m5C preventing completion of DSB repair, FMRP depletion or low expression leads to delayed repair of DSBs at transcriptionally active sites and sensitizes cancer cells to radiation in a BRCA-independent manner. Together, our findings present an m5C reader, FMRP, which acts as a coordinator between the m5C writer and eraser to promote mRNA-dependent repair and cell survival in cancer.

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Yang, H., Wang, Y., Xiang, Y., Yadav, T., Ouyang, J., Phoon, L., … Lan, L. (2022). FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation. Proceedings of the National Academy of Sciences of the United States of America, 119(12). https://doi.org/10.1073/pnas.2116251119

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