Journal Article

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

Yang, Haibo, Shi, Yi, Phoon, Laiyee, Wang, Yumin, Zou, Lee, Lan, Li, Zhu, Xueping, Xiang, Yufei, Ouyang, Jian, Yadav, Tribhuwan

2022

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Biological Sciences / Breast cancer / Cancer / Cell Biology / Cell survival / Chromatin / Cytosine / Demethylation / Deoxyribonucleic acid / Depletion / DNA / DNA damage / DNA methyltransferase / DNA repair / FMR1 protein / Fragile X Mental Retardation Protein - genetics / Fragile X Mental Retardation Protein - metabolism / Fragile X syndrome / Fragile X Syndrome - genetics / Homologous Recombination / Homology / Humans / Hybrids / Intellectual disabilities / Mixed Function Oxygenases - metabolism / Protein transport / Proteins / Proto-Oncogene Proteins - metabolism / Repair / Ribonucleic acid / RNA / RNA - genetics / RNA - metabolism / RNA modification / RNA, Messenger - genetics / RNA, Messenger - metabolism / Temporal variations / Transcription / Translocation