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

Hao Chen, Haibo Yang, Xiaolan Zhu, Tribhuwan Yadav, Jian Ouyang, Samuel S. Truesdell, Jun Tan, Yumin Wang, Meihan Duan, Leizhen Wei, Lee Zou, Arthur S. Levine, Shobha Vasudevan and Li Lan ()
Additional contact information
Hao Chen: University of Pittsburgh School of Medicine
Haibo Yang: Harvard Medical School
Xiaolan Zhu: Harvard Medical School
Tribhuwan Yadav: Harvard Medical School
Jian Ouyang: Harvard Medical School
Samuel S. Truesdell: Harvard Medical School
Jun Tan: Harvard Medical School
Yumin Wang: University of Pittsburgh School of Medicine
Meihan Duan: University of Pittsburgh School of Medicine
Leizhen Wei: University of Pittsburgh School of Medicine
Lee Zou: Harvard Medical School
Arthur S. Levine: University of Pittsburgh School of Medicine
Shobha Vasudevan: Harvard Medical School
Li Lan: University of Pittsburgh School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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 m5C at sites of DNA damage. The RNA methyltransferase TRDMT1 is recruited to DNA damage sites to promote m5C 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 m5C-modified RNA. Loss of TRDMT1 in cancer cells confers sensitivity to PARP inhibitors in vitro and in vivo. These results reveal an unexpected TRDMT1-m5C axis that promotes HR, suggesting that post-transcriptional modifications of RNA can also serve as DNA damage codes to regulate DNA repair.

Date: 2020
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DOI: 10.1038/s41467-020-16722-7

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