m 5 C modification of mRNA serves a DNA damage code to promote homologous recombination

• Published in: Nature communications Vol. 11; no. 1; p. 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: Journal Article
• Language: English
• Published: England 05.06.2020
• Subjects: Animals; Cell Line, Tumor; Cytosine - metabolism; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Breaks, Double-Stranded; Drug Resistance, Neoplasm - genetics; Gene Knockdown Techniques; Homologous Recombination; Humans; Methylation; Mice; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Rad51 Recombinase - metabolism; Rad52 DNA Repair and Recombination Protein - metabolism; RNA Processing, Post-Transcriptional - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2041-1723

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 C at sites of DNA damage. The RNA methyltransferase TRDMT1 is recruited to DNA damage sites to promote m 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 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 C axis that promotes HR, suggesting that post-transcriptional modifications of RNA can also serve as DNA damage codes to regulate DNA repair.