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

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·2020·Nature Communications
DOI 10.1038/s41467-020-16722-7PMC PMC7275041
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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 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.

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Fig. 1 m5C mRNA methylation is enriched at transcriptionally active sites with DNA damage. a U2OS-TRE cells transfected with TA-KR/TA-Cherry/tetR-KR/tetR-Cherry plasmids were exposed to light for 30 min for KR activation and allowed to recover for 1 h before harvest (scale bar: 10 μm). Quantification of frequency of cells in 500 cells with m5C foci from three independent experiments, mean ± SD (upper right). Fold increase of m5C mean intensity = mean intensity of m5C at TA-KR/mean intensity of background (n = 20, mean ± SD) (lower right). b U2OS-TRE cells were transfected with TA-KR/TA-Cherry to induce local oxidative damage or for the control condition. Cells were then stained for m5C with four different anti-m5C antibodies. Frequency of m5C-positive cells in 500 cells was quantified (n = 3, mean ± SD). c U2OS-TRE cells transfected with TA-KR were digested with RNaseH1, RNaseA, or DNase I and stained for m5C quantification (scale bar: 10 μm). d The mRNA from Flp-in 293 cells treated with or without 2 mM H2O2 for 40 min was used for m5C measurement via dot blot. Quantification of m5C levels (mean ± SD) from three independent experiments normalized with Ctrl and methylene blue is shown. e 32P-labeled mRNA monophosphate nucleosides were run on 2D gels for 2D-TLC analysis. In vitro-transcribed 4B mRNA with or without m5C was run in parallel. Representative images from three sets of independent experiments are shown with arrows showing the directions of each solvent run. Position of each nucleotide and m5C are labeled (Left). f 32P-labeled mRNA monophosphate nucleosides from U2OS cells with or without 2 mM H2O2 for 40 min were run on 2D gels for 2D-TLC analysis. Representative images from three sets of independent experiments. Associated quantification of relative increase in m5C in peroxide-treated cells compared to control, normalized to nucleotide C (right). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
Fig. 1 m5C mRNA methylation is enriched at transcriptionally active sites with DNA damage. a U2OS-TRE cells transfected with TA-KR/TA-Cherry/tetR-KR/tetR-Cherry plasmids were exposed to light for 30 min for KR activation and allowed to recover for 1 h before harvest (scale bar: 10 μm). Quantification of frequency of cells in 500 cells with m5C foci from three independent experiments, mean ± SD (upper right). Fold increase of m5C mean intensity = mean intensity of m5C at TA-KR/mean intensity of background (n = 20, mean ± SD) (lower right). b U2OS-TRE cells were transfected with TA-KR/TA-Cherry to induce local oxidative damage or for the control condition. Cells were then stained for m5C with four different anti-m5C antibodies. Frequency of m5C-positive cells in 500 cells was quantified (n = 3, mean ± SD). c U2OS-TRE cells transfected with TA-KR were digested with RNaseH1, RNaseA, or DNase I and stained for m5C quantification (scale bar: 10 μm). d The mRNA from Flp-in 293 cells treated with or without 2 mM H2O2 for 40 min was used for m5C measurement via dot blot. Quantification of m5C levels (mean ± SD) from three independent experiments normalized with Ctrl and methylene blue is shown. e 32P-labeled mRNA monophosphate nucleosides were run on 2D gels for 2D-TLC analysis. In vitro-transcribed 4B mRNA with or without m5C was run in parallel. Representative images from three sets of independent experiments are shown with arrows showing the directions of each solvent run. Position of each nucleotide and m5C are labeled (Left). f 32P-labeled mRNA monophosphate nucleosides from U2OS cells with or without 2 mM H2O2 for 40 min were run on 2D gels for 2D-TLC analysis. Representative images from three sets of independent experiments. Associated quantification of relative increase in m5C in peroxide-treated cells compared to control, normalized to nucleotide C (right). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.CC BY · PubMed Central
Fig. 2 TRDMT1 mediates m5C mRNA methylation at DNA damage sites. a U2OS-TRE cells pre-treated with the indicated siRNA were transfected with TA-KR to induce local oxidative damage and stained for m5C. The frequency of cells in 500 cells with m5C foci (n = 3, mean ± SD) is shown. b The U2OS-TRE WT and TRDMT1 KO cells were transfected with TA-KR, stained for m5C, and quantified (scale bar: 10 μm) (n = 3, mean ± SD). c WT U2OS and TRDMT1 KO cells were treated with 2 mM H2O2 for 40 min. The mRNA was then extracted from the cell lysates for m5C measurement via dot blot. Quantification of m5C levels (mean ± SD) from three independent experiments normalized with Ctrl and methylene blue is shown. d 32P-labeled monophosphate nucleosides from mRNA from WT U2OS and TRDMT1 KO cells with or without 2 mM H2O2 for 40 min were run on 2D gels for 2D-TLC analysis. Representative images from three sets of independent experiments. Associated quantification of relative increases in m5C from H2O2-treated cells were compared to the control and normalized to nucleotide C (n = 3, mean ± SD). e The TRDMT1 KO and stably rescued cell lines expressing WT TRDMT1 or the C79A mutant were transfected with TA-KR, stained for m5C, and quantified (scale bar: 10 μm) (n = 3, mean ± SD). f U2OS-TRE cells transfected with TA-KR/TA-Cherry/tetR-KR/tetR-Cherry and GFP-TRDMT1/GFP-NSUN2 plasmids were light-irradiated and allowed to recover for 1 h before fixation and were quantified (scale bar: 10 μm) (n = 10, mean ± SD). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
Fig. 2 TRDMT1 mediates m5C mRNA methylation at DNA damage sites. a U2OS-TRE cells pre-treated with the indicated siRNA were transfected with TA-KR to induce local oxidative damage and stained for m5C. The frequency of cells in 500 cells with m5C foci (n = 3, mean ± SD) is shown. b The U2OS-TRE WT and TRDMT1 KO cells were transfected with TA-KR, stained for m5C, and quantified (scale bar: 10 μm) (n = 3, mean ± SD). c WT U2OS and TRDMT1 KO cells were treated with 2 mM H2O2 for 40 min. The mRNA was then extracted from the cell lysates for m5C measurement via dot blot. Quantification of m5C levels (mean ± SD) from three independent experiments normalized with Ctrl and methylene blue is shown. d 32P-labeled monophosphate nucleosides from mRNA from WT U2OS and TRDMT1 KO cells with or without 2 mM H2O2 for 40 min were run on 2D gels for 2D-TLC analysis. Representative images from three sets of independent experiments. Associated quantification of relative increases in m5C from H2O2-treated cells were compared to the control and normalized to nucleotide C (n = 3, mean ± SD). e The TRDMT1 KO and stably rescued cell lines expressing WT TRDMT1 or the C79A mutant were transfected with TA-KR, stained for m5C, and quantified (scale bar: 10 μm) (n = 3, mean ± SD). f U2OS-TRE cells transfected with TA-KR/TA-Cherry/tetR-KR/tetR-Cherry and GFP-TRDMT1/GFP-NSUN2 plasmids were light-irradiated and allowed to recover for 1 h before fixation and were quantified (scale bar: 10 μm) (n = 10, mean ± SD). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.CC BY · PubMed Central
Fig. 3 TRDMT1 is required for damage removal and HR. a WT or TRDMT1 KO U2OS-TRE cells were transfected with TA-KR and stained for γH2AX at the indicated timepoint after damage (n = 3, mean ± SD). b Stable expression of Myc-tagged TRDMT1 in TRDMT1 KO U2OS-TRE cell lines shown in Western blots. Expression of β-actin is shown as a positive control. c U2OS-TRE WT, TRDMT1 KO, and TRDMT1 stably expressing cells were stained for γH2AX after damage caused by TA-KR at the indicated timepoint (n = 3, mean ± SD). d DR-GFP cells were pre-treated with siTRDMT1, siBRCA1, or control siRNA and then transfected with the NLS-I-SceI plasmid to induce DSBs. The GFP-positive population was analyzed by flow cytometry (n = 3, mean ± SD). e WT or TRDMT1 KO U2OS cells were co-transfected with CRISPR/Cas9-sgLMNA, LMNA-mClover, and mCherry plasmids. The fraction of mClover-positive cells in the mCherry-positive population was analyzed by flow cytometry (n = 3, mean ± SD). f EJ5-GFP cells were pre-treated with siTRDMT1 or control siRNA and then transfected with the NLS-I-SceI plasmid to induce DSBs. The GFP-positive population was analyzed by flow cytometry (n = 3, mean ± SD). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
Fig. 3 TRDMT1 is required for damage removal and HR. a WT or TRDMT1 KO U2OS-TRE cells were transfected with TA-KR and stained for γH2AX at the indicated timepoint after damage (n = 3, mean ± SD). b Stable expression of Myc-tagged TRDMT1 in TRDMT1 KO U2OS-TRE cell lines shown in Western blots. Expression of β-actin is shown as a positive control. c U2OS-TRE WT, TRDMT1 KO, and TRDMT1 stably expressing cells were stained for γH2AX after damage caused by TA-KR at the indicated timepoint (n = 3, mean ± SD). d DR-GFP cells were pre-treated with siTRDMT1, siBRCA1, or control siRNA and then transfected with the NLS-I-SceI plasmid to induce DSBs. The GFP-positive population was analyzed by flow cytometry (n = 3, mean ± SD). e WT or TRDMT1 KO U2OS cells were co-transfected with CRISPR/Cas9-sgLMNA, LMNA-mClover, and mCherry plasmids. The fraction of mClover-positive cells in the mCherry-positive population was analyzed by flow cytometry (n = 3, mean ± SD). f EJ5-GFP cells were pre-treated with siTRDMT1 or control siRNA and then transfected with the NLS-I-SceI plasmid to induce DSBs. The GFP-positive population was analyzed by flow cytometry (n = 3, mean ± SD). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.CC BY · PubMed Central
Fig. 4 RAD52 is a m5C reader. a U2OS-TRE WT and TRDMT1 KO cells were transfected with TA-KR and stained for RAD51 1 h after light irradiation. Representative figures were shown (scale bar: 10 μm). b U2OS-TRE WT, TRDMT1 KO, and TRDMT1 stably rescued cell lines were transfected with TA-KR. and stained for RAD51 1 h after light irradiation. Fold increase of RAD51 foci intensity was calculated (n = 25, mean ± SD). c U2OS-TRE WT and TRDMT1 KO cells were transfected with TA-KR and GFP-RAD52 and fixed 1 h after light irradiation. Representative figures were shown (scale bar: 10 μm). d U2OS-TRE WT, TRDMT1 KO, and TRDMT1 stably rescued cell lines were co-transfected with GFP-RAD52 and TA-KR and quantified for RAD52 foci frequency (n = 3, mean ± SD). e RNA oligos with or without m5C modification and their complementary DNA oligos were chemically synthesized for RAD52 binding experiments. f RAD52 protein in the cell lysate was pulled down by biotin-labeled DNA:RNA hybrids, with or without m5C RNA modification, coated on streptavidin magnetic beads. g The binding of RAD52 protein to DNA:RNA hybrids with or without m5C RNA modification was measured in electrophoretic mobility shift assays and quantified (n = 3, mean ± SD). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
Fig. 4 RAD52 is a m5C reader. a U2OS-TRE WT and TRDMT1 KO cells were transfected with TA-KR and stained for RAD51 1 h after light irradiation. Representative figures were shown (scale bar: 10 μm). b U2OS-TRE WT, TRDMT1 KO, and TRDMT1 stably rescued cell lines were transfected with TA-KR. and stained for RAD51 1 h after light irradiation. Fold increase of RAD51 foci intensity was calculated (n = 25, mean ± SD). c U2OS-TRE WT and TRDMT1 KO cells were transfected with TA-KR and GFP-RAD52 and fixed 1 h after light irradiation. Representative figures were shown (scale bar: 10 μm). d U2OS-TRE WT, TRDMT1 KO, and TRDMT1 stably rescued cell lines were co-transfected with GFP-RAD52 and TA-KR and quantified for RAD52 foci frequency (n = 3, mean ± SD). e RNA oligos with or without m5C modification and their complementary DNA oligos were chemically synthesized for RAD52 binding experiments. f RAD52 protein in the cell lysate was pulled down by biotin-labeled DNA:RNA hybrids, with or without m5C RNA modification, coated on streptavidin magnetic beads. g The binding of RAD52 protein to DNA:RNA hybrids with or without m5C RNA modification was measured in electrophoretic mobility shift assays and quantified (n = 3, mean ± SD). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.CC BY · PubMed Central
Fig. 5 TRDMT1 inhibition sensitizes cells to radiation and PARPi. a Clinical and RNA-seq gene expression data were downloaded from TCGA. RSI was calculated by a rank-based linear regression algorithm. The median value of BRCA1 and TRDMT1 TPM was defined as the cutoff to classify patients into high expression and low expression groups (n = 1091, mean ±SD). b WT, TRDMT1 KO U2OS, or siBRCA1 cells were treated with Olaparib at the indicated dose. The survival rate was measured via the colony formation assay (n = 3, mean ± SEM). c Tumor volume in mice injected with LV-shTRDMT1 or LV-NC pre-treated MDA-MB-231 cells at the indicated time (n = 3, mean ± SEM). One week after injection, 50 mg/kg Olaparib or saline was intraperitoneally injected into the xenograft tumors once every other day. d Tumor volume in mice injected with LV-shTRDMT1 or LV-NC pre-treated MDA-MB-231 cells at day 12 after PARPi treatment (n = 3, mean ± SEM). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
Fig. 5 TRDMT1 inhibition sensitizes cells to radiation and PARPi. a Clinical and RNA-seq gene expression data were downloaded from TCGA. RSI was calculated by a rank-based linear regression algorithm. The median value of BRCA1 and TRDMT1 TPM was defined as the cutoff to classify patients into high expression and low expression groups (n = 1091, mean ±SD). b WT, TRDMT1 KO U2OS, or siBRCA1 cells were treated with Olaparib at the indicated dose. The survival rate was measured via the colony formation assay (n = 3, mean ± SEM). c Tumor volume in mice injected with LV-shTRDMT1 or LV-NC pre-treated MDA-MB-231 cells at the indicated time (n = 3, mean ± SEM). One week after injection, 50 mg/kg Olaparib or saline was intraperitoneally injected into the xenograft tumors once every other day. d Tumor volume in mice injected with LV-shTRDMT1 or LV-NC pre-treated MDA-MB-231 cells at day 12 after PARPi treatment (n = 3, mean ± SEM). Statistical analysis was performed with the unpaired two tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.CC BY · PubMed Central

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Authors
Chen, H., Yang, H., Zhu, X., Yadav, T., Ouyang, J., Truesdell, S. S., Tan, J., Wang, Y., Duan, M., Wei, L., Zou, L., Levine, A. S., Vasudevan, S., & Lan, L.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-06-05
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-16722-7
PMC
PMC7275041
Cited by
179
References
7
Language
en
Licence
Funders
U.S. Department of Health & Human Services | National Institutes of Health (GM118833)

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Chen, H., Yang, H., Zhu, X., Yadav, T., Ouyang, J., Truesdell, S. S., Tan, J., Wang, Y., Duan, M., Wei, L., Zou, L., Levine, A. S., Vasudevan, S., & Lan, L. (2020). m5C modification of mRNA serves a DNA damage code to promote homologous recombination. Nature Communications. https://doi.org/10.1038/s41467-020-16722-7