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

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.

5-methylcytosine modification byPlasmodiumNSUN2 stabilizes mRNA and mediates the development of gametocytes

“…Modification of mRNA by m C is important for diverse biological processes including the progression of bladder cancer, HIV-1 infection, and developmental progressions in zebrafish, Arabidopsis thaliana, and rice (13,(17)(18)(19), suggesting that cytosine methylation is a powerful regulator of cellular processes at the epitranscriptomic level (16). In other studies, pathways involving m 5 C-modified transcripts have been found to include DNA repair and homologous recombination (20). Specific methyltransferases (m 5 C writers) in various species include NSUN2 in humans, TRM48 in Arabidopsis thaliana, and OsNSUN2 in rice.…”

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“…A recent report showed that DNMT2 (Figure 3B) is recruited to DNA damage sites, where it deposits m 5 C onto the DNA damage-associated mRNAs and contributes to R-loop formation. The m 5 C and DNMT2-mediated R-loops facilitate the homologous recombination (HR) and DNA repair of DSBs [247].…”

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“…Repair with high fidelity is essential for genetic stability and good health [67]. In some cases, mRNA serves as a DNA damage code and promotes homologous recombination [68]. As a result, the entrance of any foreign mRNA inside human cells poses a risk to the stability of the cellular genome of the recipient.…”