m5C modification of mRNA serves a DNA damage code to promote homologous recombination

• Published in: Nature communications 2020-06, Vol.11 (1), p.2834-2834, Article 2834
• Main Authors: Chen, Hao, Yang, Haibo, Zhu, Xiaolan, Yadav, Tribhuwan, Ouyang, Jian, Truesdell, Samuel S., Tan, Jun, Wang, Yumin, Duan, Meihan, Wei, Leizhen, Zou, Lee, Levine, Arthur S., Vasudevan, Shobha, Lan, Li
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/89; 14; 14/35; 14/63; 38/22; 38/90; 631/337/1427/2190; 631/337/149; 631/337/1645/2570; 631/337/176; 631/67/2324; 82/80; Damage localization; Deoxyribonucleic acid; DNA; DNA damage; DNA methyltransferase; DNA repair; Homologous recombination; Homologous recombination repair; Homology; Humanities and Social Sciences; Hybrids; multidisciplinary; Poly(ADP-ribose) polymerase; Post-transcription; Post-translation; Proteins; Rad52 protein; Reactive oxygen species; Recruitment; Repair; Ribonucleic acid; RNA; RNA modification; Science; Science (multidisciplinary); Sensitivity; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16722-7

Recruitment of DNA repair proteins to DNA damage sites is a critical step for DNA repair. Post-translational modifications of proteins at DNA damage sites serve as DNA damage codes to recruit specific DNA repair factors. Here, we show that mRNA is locally modified by m 5 C at sites of DNA damage. The RNA methyltransferase TRDMT1 is recruited to DNA damage sites to promote m 5 C induction. Loss of TRDMT1 compromises homologous recombination (HR) and increases cellular sensitivity to DNA double-strand breaks (DSBs). In the absence of TRDMT1, RAD51 and RAD52 fail to localize to sites of reactive oxygen species (ROS)-induced DNA damage. In vitro, RAD52 displays an increased affinity for DNA:RNA hybrids containing m 5 C-modified RNA. Loss of TRDMT1 in cancer cells confers sensitivity to PARP inhibitors in vitro and in vivo. These results reveal an unexpected TRDMT1-m 5 C axis that promotes HR, suggesting that post-transcriptional modifications of RNA can also serve as DNA damage codes to regulate DNA repair. Post-translational modifications of proteins at DNA damage sites can facilitate the recruitment of DNA repair factors. Here, the authors show that mRNA is locally modified with m 5 C at sites of DNA damage by the RNA methyltransferase TRDMT1 to promote homologous recombination repair.