The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability
Abstract
1. Introduction
2. Dynamic Regulation of m6A on R-Loops
2.1. Recruitment of m6A Methyltransferase Complexes to R-Loops: Role of RNA-Binding Proteins
2.2. Removal of m6A on R-Loops by FTO and ALKBH5 Demethylases
2.3. Recognition of m6A-Modified R-Loops by Reader Proteins
3. The Regulatory Role of m6A in R-Loop Dynamics
3.1. m6A Promotes R-Loop Formation
3.2. Stabilization of R-Loops by m6A and Reader Protein Binding
3.3. m6A-Mediated R-Loop Resolution
4. Impact of m6A Modification on R-Loops in Genome Stability
5. Functional Implications for m6A and R-Loops in Disease Pathogenesis
Gene or Protein | Function | Disease | Reference |
---|---|---|---|
DDX41 | Mutation in RNA helicase hinders YTHDC1 recruitment to R-loops, leading to accumulation of DNA damage and R-loops | Myelodysplastic syndrome | [42] |
EWS-FLI1 | Promotes R-loop accumulation through enhanced RNA synthesis | Ewing sarcoma | [73] |
TERRA | m6A-modified TERRA promotes homologous recombination and protection of telomeres in cancer cells | Neuroblastoma | [61] |
ARID1A | Involved in METTL3-m6A axis to enhance RNase-H1-mediated resolution of R-loops | ARID1A altered cancers | [45,70] |
SETX | SETX deficiency increased R-loops and DNA DSBs | Ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4) | [74] |
circPOLR2B | m6A-modified circPOLR2B interacts with YTHDC1for nuclear transport resulting in reduced R-loop formation in nucleus with parent gene POLR2B | Glioma | [43] |
U2AF1, SRSF2, SF3B1 | Mutations in splicing factors lead to aberrant accumulation of R-loops | Myelodysplastic syndromes | [75,76] |
RBM15 | Involved in R-loop recognition and recruitment of METTL3 to R-loops for m6A modification deposition | Prostate cancer | [41] |
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- García-Muse, T.; Aguilera, A. R Loops: From Physiological to Pathological Roles. Cell 2019, 179, 604–618. [Google Scholar] [CrossRef] [PubMed]
- Hegazy, Y.A.; Fernando, C.M.; Tran, E.J. The Balancing Act of R-Loop Biology: The Good, the Bad, and the Ugly. J. Biol. Chem. 2020, 295, 905–913. [Google Scholar] [CrossRef]
- Sanz, L.A.; Hartono, S.R.; Lim, Y.W.; Steyaert, S.; Rajpurkar, A.; Ginno, P.A.; Xu, X.; Chédin, F. Prevalent, Dynamic, and Conserved R-Loop Structures Associate with Specific Epigenomic Signatures in Mammals. Mol. Cell 2016, 63, 167–178. [Google Scholar] [CrossRef] [PubMed]
- Ginno, P.A.; Lott, P.L.; Christensen, H.C.; Korf, I.; Chédin, F. R-Loop Formation Is a Distinctive Characteristic of Unmethylated Human CpG Island Promoters. Mol. Cell 2012, 45, 814–825. [Google Scholar] [CrossRef]
- Arab, K.; Karaulanov, E.; Musheev, M.; Trnka, P.; Schäfer, A.; Grummt, I.; Niehrs, C. GADD45A Binds R-Loops and Recruits TET1 to CpG Island Promoters. Nat. Genet. 2019, 51, 217–223. [Google Scholar] [CrossRef] [PubMed]
- Feretzaki, M.; Pospisilova, M.; Valador Fernandes, R.; Lunardi, T.; Krejci, L.; Lingner, J. RAD51-Dependent Recruitment of TERRA lncRNA to Telomeres through R-Loops. Nature 2020, 587, 303–308. [Google Scholar] [CrossRef]
- Graf, M.; Bonetti, D.; Lockhart, A.; Serhal, K.; Kellner, V.; Maicher, A.; Jolivet, P.; Teixeira, M.T.; Luke, B. Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle. Cell 2017, 170, 72–85.e14. [Google Scholar] [CrossRef]
- El Hage, A.; French, S.L.; Beyer, A.L.; Tollervey, D. Loss of Topoisomerase I Leads to R-Loop-Mediated Transcriptional Blocks during Ribosomal RNA Synthesis. Genes Dev. 2010, 24, 1546–1558. [Google Scholar] [CrossRef]
- Skourti-Stathaki, K.; Kamieniarz-Gdula, K.; Proudfoot, N.J. R-Loops Induce Repressive Chromatin Marks over Mammalian Gene Terminators. Nature 2014, 516, 436–439. [Google Scholar] [CrossRef]
- Qiu, Y.; Man, C.; Zhu, L.; Zhang, S.; Wang, X.; Gong, D.; Fan, Y. R-Loops’ m6A Modification and Its Roles in Cancers. Mol. Cancer 2024, 23, 232. [Google Scholar] [CrossRef]
- Grunseich, C.; Wang, I.X.; Watts, J.A.; Burdick, J.T.; Guber, R.D.; Zhu, Z.; Bruzel, A.; Lanman, T.; Chen, K.; Schindler, A.B.; et al. Senataxin Mutation Reveals How R-Loops Promote Transcription by Blocking DNA Methylation at Gene Promoters. Mol. Cell 2018, 69, 426–437.e7. [Google Scholar] [CrossRef]
- Wiedemann, E.-M.; Peycheva, M.; Pavri, R. DNA Replication Origins in Immunoglobulin Switch Regions Regulate Class Switch Recombination in an R-Loop-Dependent Manner. Cell Rep. 2016, 17, 2927–2942. [Google Scholar] [CrossRef] [PubMed]
- Santos-Pereira, J.M.; Aguilera, A. R Loops: New Modulators of Genome Dynamics and Function. Nat. Rev. Genet. 2015, 16, 583–597. [Google Scholar] [CrossRef]
- Salas-Armenteros, I.; Pérez-Calero, C.; Bayona-Feliu, A.; Tumini, E.; Luna, R.; Aguilera, A. Human THO-Sin3A Interaction Reveals New Mechanisms to Prevent R-Loops That Cause Genome Instability. EMBO J. 2017, 36, 3532–3547. [Google Scholar] [CrossRef]
- Wahba, L.; Amon, J.D.; Koshland, D.; Vuica-Ross, M. RNase H and Multiple RNA Biogenesis Factors Cooperate to Prevent RNA:DNA Hybrids from Generating Genome Instability. Mol. Cell 2011, 44, 978–988. [Google Scholar] [CrossRef] [PubMed]
- El Hage, A.; Webb, S.; Kerr, A.; Tollervey, D. Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria. PLoS Genet. 2014, 10, e1004716. [Google Scholar] [CrossRef]
- Kim, A.; Wang, G.G. R-Loop and Its Functions at the Regulatory Interfaces between Transcription and (Epi)Genome. Biochim. Biophys. Acta Gene Regul. Mech. 2021, 1864, 194750. [Google Scholar] [CrossRef] [PubMed]
- Brickner, J.R.; Garzon, J.L.; Cimprich, K.A. Walking a Tightrope: The Complex Balancing Act of R-Loops in Genome Stability. Mol. Cell 2022, 82, 2267–2297. [Google Scholar] [CrossRef]
- Skourti-Stathaki, K.; Proudfoot, N.J. A Double-Edged Sword: R Loops as Threats to Genome Integrity and Powerful Regulators of Gene Expression. Genes Dev. 2014, 28, 1384–1396. [Google Scholar] [CrossRef]
- Dominissini, D.; Moshitch-Moshkovitz, S.; Schwartz, S.; Salmon-Divon, M.; Ungar, L.; Osenberg, S.; Cesarkas, K.; Jacob-Hirsch, J.; Amariglio, N.; Kupiec, M.; et al. Topology of the Human and Mouse m6A RNA Methylomes Revealed by m6A-Seq. Nature 2012, 485, 201–206. [Google Scholar] [CrossRef]
- Jia, G.; Fu, Y.; Zhao, X.; Dai, Q.; Zheng, G.; Yang, Y.; Yi, C.; Lindahl, T.; Pan, T.; Yang, Y.-G.; et al. N6-Methyladenosine in Nuclear RNA Is a Major Substrate of the Obesity-Associated FTO. Nat. Chem. Biol. 2011, 7, 885–887. [Google Scholar] [CrossRef] [PubMed]
- Zheng, G.; Dahl, J.A.; Niu, Y.; Fedorcsak, P.; Huang, C.-M.; Li, C.J.; Vågbø, C.B.; Shi, Y.; Wang, W.-L.; Song, S.-H.; et al. ALKBH5 Is a Mammalian RNA Demethylase That Impacts RNA Metabolism and Mouse Fertility. Mol. Cell 2013, 49, 18–29. [Google Scholar] [CrossRef]
- Wang, X.; Lu, Z.; Gomez, A.; Hon, G.C.; Yue, Y.; Han, D.; Fu, Y.; Parisien, M.; Dai, Q.; Jia, G.; et al. N6-Methyladenosine-Dependent Regulation of Messenger RNA Stability. Nature 2014, 505, 117–120. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Yue, Y.; Han, D.; Wang, X.; Fu, Y.; Zhang, L.; Jia, G.; Yu, M.; Lu, Z.; Deng, X.; et al. A METTL3-METTL14 Complex Mediates Mammalian Nuclear RNA N6-Adenosine Methylation. Nat. Chem. Biol. 2014, 10, 93–95. [Google Scholar] [CrossRef]
- Meyer, K.D.; Jaffrey, S.R. Rethinking m6A Readers, Writers, and Erasers. Annu. Rev. Cell Dev. Biol. 2017, 33, 319–342. [Google Scholar] [CrossRef]
- Frye, M.; Harada, B.T.; Behm, M.; He, C. RNA Modifications Modulate Gene Expression during Development. Science 2018, 361, 1346–1349. [Google Scholar] [CrossRef] [PubMed]
- He, L.; Li, H.; Wu, A.; Peng, Y.; Shu, G.; Yin, G. Functions of N6-Methyladenosine and Its Role in Cancer. Mol. Cancer 2019, 18, 176. [Google Scholar] [CrossRef]
- An, Y.; Duan, H. The Role of m6A RNA Methylation in Cancer Metabolism. Mol. Cancer 2022, 21, 14. [Google Scholar] [CrossRef]
- Abakir, A.; Giles, T.C.; Cristini, A.; Foster, J.M.; Dai, N.; Starczak, M.; Rubio-Roldan, A.; Li, M.; Eleftheriou, M.; Crutchley, J.; et al. N6-Methyladenosine Regulates the Stability of RNA:DNA Hybrids in Human Cells. Nat. Genet. 2020, 52, 48–55. [Google Scholar] [CrossRef]
- Yang, X.; Liu, Q.-L.; Xu, W.; Zhang, Y.-C.; Yang, Y.; Ju, L.-F.; Chen, J.; Chen, Y.-S.; Li, K.; Ren, J.; et al. m6A Promotes R-Loop Formation to Facilitate Transcription Termination. Cell Res. 2019, 29, 1035–1038. [Google Scholar] [CrossRef]
- Xu, C.; Wu, Z.; Duan, H.-C.; Fang, X.; Jia, G.; Dean, C. R-Loop Resolution Promotes Co-Transcriptional Chromatin Silencing. Nat. Commun. 2021, 12, 1790. [Google Scholar] [CrossRef] [PubMed]
- Kang, H.J.; Cheon, N.Y.; Park, H.; Jeong, G.W.; Ye, B.J.; Yoo, E.J.; Lee, J.H.; Hur, J.-H.; Lee, E.-A.; Kim, H.; et al. TonEBP Recognizes R-Loops and Initiates m6A RNA Methylation for R-Loop Resolution. Nucleic Acids Res. 2021, 49, 269–284. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Lin, S.; Chen, H.; Zheng, X. Cross-Regulation of RNA Methylation Modifications and R-Loops: From Molecular Mechanisms to Clinical Implications. Cell. Mol. Life Sci. CMLS 2024, 82, 1. [Google Scholar] [CrossRef]
- Hao, J.-D.; Liu, Q.-L.; Liu, M.-X.; Yang, X.; Wang, L.-M.; Su, S.-Y.; Xiao, W.; Zhang, M.-Q.; Zhang, Y.-C.; Zhang, L.; et al. DDX21 Mediates Co-Transcriptional RNA m6A Modification to Promote Transcription Termination and Genome Stability. Mol. Cell 2024, 84, 1711–1726.e11. [Google Scholar] [CrossRef] [PubMed]
- Vaid, R.; Thombare, K.; Mendez, A.; Burgos-Panadero, R.; Djos, A.; Jachimowicz, D.; Lundberg, K.I.; Bartenhagen, C.; Kumar, N.; Tümmler, C.; et al. METTL3 Drives Telomere Targeting of TERRA lncRNA through m6A-Dependent R-Loop Formation: A Therapeutic Target for ALT-Positive Neuroblastoma. Nucleic Acids Res. 2024, 52, 2648–2671. [Google Scholar] [CrossRef]
- Zhang, C.; Chen, L.; Peng, D.; Jiang, A.; He, Y.; Zeng, Y.; Xie, C.; Zhou, H.; Luo, X.; Liu, H.; et al. METTL3 and N6-Methyladenosine Promote Homologous Recombination-Mediated Repair of DSBs by Modulating DNA-RNA Hybrid Accumulation. Mol. Cell 2020, 79, 425–442.e7. [Google Scholar] [CrossRef]
- Jiang, X.; Liu, B.; Nie, Z.; Duan, L.; Xiong, Q.; Jin, Z.; Yang, C.; Chen, Y. The Role of m6A Modification in the Biological Functions and Diseases. Signal Transduct. Target. Ther. 2021, 6, 74. [Google Scholar] [CrossRef]
- Abakir, A.; Ruzov, A. A Model for a Dual Function of N6-Methyladenosine in R-Loop Regulation. Nat. Genet. 2024, 56, 1995–1998. [Google Scholar] [CrossRef]
- Engel, J.D.; von Hippel, P.H. Effects of Methylation on the Stability of Nucleic Acid Conformations. Studies at the Polymer Level. J. Biol. Chem. 1978, 253, 927–934. [Google Scholar] [CrossRef]
- Höfler, S.; Duss, O. Interconnections between m6A RNA Modification, RNA Structure, and Protein–RNA Complex Assembly. Life Sci. Alliance 2023, 7, e202302240. [Google Scholar] [CrossRef]
- Ying, Y.; Wu, Y.; Zhang, F.; Tang, Y.; Yi, J.; Ma, X.; Li, J.; Chen, D.; Wang, X.; Liu, X.; et al. Co-Transcriptional R-Loops-Mediated Epigenetic Regulation Drives Growth Retardation and Docetaxel Chemosensitivity Enhancement in Advanced Prostate Cancer. Mol. Cancer 2024, 23, 79. [Google Scholar] [CrossRef]
- Hwang, W.C.; Park, K.; Park, S.; Cheon, N.Y.; Lee, J.Y.; Hwang, T.; Lee, S.; Lee, J.-M.; Ju, M.K.; Lee, J.R.; et al. Impaired Binding Affinity of YTHDC1 with METTL3/METTL14 Results in R-Loop Accumulation in Myelodysplastic Neoplasms with DDX41 Mutation. Leukemia 2024, 38, 1353–1364. [Google Scholar] [CrossRef] [PubMed]
- Lin, H.; Cui, Z.; Tiange, E.; Xu, H.; Wang, D.; Wang, P.; Ruan, X.; Liu, L.; Xue, Y. M6A-Methylated circPOLR2B Forms an R-Loop and Regulates the Biological Behavior of Glioma Stem Cells through Positive Feedback Loops. Cell Death Dis. 2024, 15, 554. [Google Scholar] [CrossRef]
- Ke, S.; Pandya-Jones, A.; Saito, Y.; Fak, J.J.; Vågbø, C.B.; Geula, S.; Hanna, J.H.; Black, D.L.; Darnell, J.E.; Darnell, R.B. m6A mRNA Modifications Are Deposited in Nascent Pre-mRNA and Are Not Required for Splicing but Do Specify Cytoplasmic Turnover. Genes Dev. 2017, 31, 990–1006. [Google Scholar] [CrossRef]
- Zhang, J.; Chen, F.; Tang, M.; Xu, W.; Tian, Y.; Liu, Z.; Shu, Y.; Yang, H.; Zhu, Q.; Lu, X.; et al. The ARID1A-METTL3-m6A Axis Ensures Effective RNase H1-Mediated Resolution of R-Loops and Genome Stability. Cell Rep. 2024, 43, 113779. [Google Scholar] [CrossRef] [PubMed]
- Xu, C.; Liu, K.; Tempel, W.; Demetriades, M.; Aik, W.; Schofield, C.J.; Min, J. Structures of Human ALKBH5 Demethylase Reveal a Unique Binding Mode for Specific Single-Stranded N6-Methyladenosine RNA Demethylation. J. Biol. Chem. 2014, 289, 17299–17311. [Google Scholar] [CrossRef]
- Nabeel-Shah, S.; Pu, S.; Burke, G.L.; Ahmed, N.; Braunschweig, U.; Farhangmehr, S.; Lee, H.; Wu, M.; Ni, Z.; Tang, H.; et al. Recruitment of the m6A/m6Am Demethylase FTO to Target RNAs by the Telomeric Zinc Finger Protein ZBTB48. Genome Biol. 2024, 25, 246. [Google Scholar] [CrossRef] [PubMed]
- Zheng, Q.; Hou, J.; Zhou, Y.; Li, Z.; Cao, X. The RNA Helicase DDX46 Inhibits Innate Immunity by Entrapping m6A-Demethylated Antiviral Transcripts in the Nucleus. Nat. Immunol. 2017, 18, 1094–1103. [Google Scholar] [CrossRef]
- Yang, Y.; Hsu, P.J.; Chen, Y.-S.; Yang, Y.-G. Dynamic Transcriptomic m6A Decoration: Writers, Erasers, Readers and Functions in RNA Metabolism. Cell Res. 2018, 28, 616–624. [Google Scholar] [CrossRef]
- Xu, C.; Liu, K.; Ahmed, H.; Loppnau, P.; Schapira, M.; Min, J. Structural Basis for the Discriminative Recognition of N6-Methyladenosine RNA by the Human YT521-B Homology Domain Family of Proteins. J. Biol. Chem. 2015, 290, 24902–24913. [Google Scholar] [CrossRef]
- Huang, H.; Weng, H.; Sun, W.; Qin, X.; Shi, H.; Wu, H.; Zhao, B.S.; Mesquita, A.; Liu, C.; Yuan, C.L.; et al. Recognition of RNA N6-Methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation. Nat. Cell Biol. 2018, 20, 285–295. [Google Scholar] [CrossRef] [PubMed]
- Liu, N.; Dai, Q.; Zheng, G.; He, C.; Parisien, M.; Pan, T. N6-Methyladenosine-Dependent RNA Structural Switches Regulate RNA–Protein Interactions. Nature 2015, 518, 560–564. [Google Scholar] [CrossRef]
- Spitale, R.C.; Flynn, R.A.; Zhang, Q.C.; Crisalli, P.; Lee, B.; Jung, J.-W.; Kuchelmeister, H.Y.; Batista, P.J.; Torre, E.A.; Kool, E.T.; et al. Structural Imprints in Vivo Decode RNA Regulatory Mechanisms. Nature 2015, 519, 486–490. [Google Scholar] [CrossRef]
- Hamperl, S.; Bocek, M.J.; Saldivar, J.C.; Swigut, T.; Cimprich, K.A. Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses. Cell 2017, 170, 774–786.e19. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Ying, Y.; Zhang, F.; Shu, X.; Qi, Z.; Wang, J.; Liu, Z.; Tang, Y.; Sun, J.; Yi, J.; et al. NSUN2-Mediated R-Loop Stabilization as a Key Driver of Bladder Cancer Progression and Cisplatin Sensitivity. Cancer Lett. 2024, 611, 217416. [Google Scholar] [CrossRef]
- Proudfoot, N.J. Transcriptional Termination in Mammals: Stopping the RNA Polymerase II Juggernaut. Science 2016, 352, aad9926. [Google Scholar] [CrossRef]
- Thomas, M.; White, R.L.; Davis, R.W. Hybridization of RNA to Double-Stranded DNA: Formation of R-Loops. Proc. Natl. Acad. Sci. USA 1976, 73, 2294–2298. [Google Scholar] [CrossRef]
- Song, X.; Xu, Y.; Li, M.; Guan, X.; Liu, H.; Zhang, J.; Sun, H.; Ma, C.; Zhang, L.; Zhao, X.; et al. SRSF4-Associated ca-circFOXP1 Regulates Hypoxia-Induced PASMC Proliferation by the Formation of R Loop With Host Gene. Arterioscler. Thromb. Vasc. Biol. 2025, 45, e118–e135. [Google Scholar] [CrossRef] [PubMed]
- Kristensen, L.S.; Andersen, M.S.; Stagsted, L.V.W.; Ebbesen, K.K.; Hansen, T.B.; Kjems, J. The Biogenesis, Biology and Characterization of Circular RNAs. Nat. Rev. Genet. 2019, 20, 675–691. [Google Scholar] [CrossRef]
- Zhou, W.-Y.; Cai, Z.-R.; Liu, J.; Wang, D.-S.; Ju, H.-Q.; Xu, R.-H. Circular RNA: Metabolism, Functions and Interactions with Proteins. Mol. Cancer 2020, 19, 172. [Google Scholar] [CrossRef]
- Chen, L.; Zhang, C.; Ma, W.; Huang, J.; Zhao, Y.; Liu, H. METTL3-Mediated m6A Modification Stabilizes TERRA and Maintains Telomere Stability. Nucleic Acids Res. 2022, 50, 11619–11634. [Google Scholar] [CrossRef] [PubMed]
- López de Silanes, I.; Graña, O.; De Bonis, M.L.; Dominguez, O.; Pisano, D.G.; Blasco, M.A. Identification of TERRA Locus Unveils a Telomere Protection Role through Association to Nearly All Chromosomes. Nat. Commun. 2014, 5, 4723. [Google Scholar] [CrossRef] [PubMed]
- Su, X.A.; Freudenreich, C.H. Cytosine Deamination and Base Excision Repair Cause R-Loop–Induced CAG Repeat Fragility and Instability in Saccharomyces Cerevisiae. Proc. Natl. Acad. Sci. USA 2017, 114, E8392–E8401. [Google Scholar] [CrossRef] [PubMed]
- Sollier, J.; Stork, C.T.; García-Rubio, M.L.; Paulsen, R.D.; Aguilera, A.; Cimprich, K.A. Transcription-Coupled Nucleotide Excision Repair Factors Promote R-Loop-Induced Genome Instability. Mol. Cell 2014, 56, 777–785. [Google Scholar] [CrossRef]
- Ohle, C.; Tesorero, R.; Schermann, G.; Dobrev, N.; Sinning, I.; Fischer, T. Transient RNA-DNA Hybrids Are Required for Efficient Double-Strand Break Repair. Cell 2016, 167, 1001–1013.e7. [Google Scholar] [CrossRef]
- Cho, N.W.; Dilley, R.L.; Lampson, M.A.; Greenberg, R.A. Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis. Cell 2014, 159, 108–121. [Google Scholar] [CrossRef]
- Fernandes, R.V.; Feretzaki, M.; Lingner, J. The Makings of TERRA R-Loops at Chromosome Ends. Cell Cycle Georget. Tex 2021, 20, 1745–1759. [Google Scholar] [CrossRef]
- Beuten, J.; Garcia, D.; Brand, T.C.; He, X.; Balic, I.; Canby-Hagino, E.; Troyer, D.A.; Baillargeon, J.; Hernandez, J.; Thompson, I.M.; et al. Semaphorin 3B and 3F Single Nucleotide Polymorphisms Are Associated with Prostate Cancer Risk and Poor Prognosis. J. Urol. 2009, 182, 1614–1620. [Google Scholar] [CrossRef]
- Wu, G. Clinical Relevance of Semaphorin-3F in Patients with Prostate Cancer. Clin. Investig. Med. Med. Clin. Exp. 2019, 42, E64–E69. [Google Scholar] [CrossRef]
- Mullen, J.; Kato, S.; Sicklick, J.K.; Kurzrock, R. Targeting ARID1A Mutations in Cancer. Cancer Treat. Rev. 2021, 100, 102287. [Google Scholar] [CrossRef]
- Fontana, B.; Gallerani, G.; Salamon, I.; Pace, I.; Roncarati, R.; Ferracin, M. ARID1A in Cancer: Friend or Foe? Front. Oncol. 2023, 13, 1136248. [Google Scholar] [CrossRef] [PubMed]
- Wilson, B.G.; Roberts, C.W.M. SWI/SNF Nucleosome Remodellers and Cancer. Nat. Rev. Cancer 2011, 11, 481–492. [Google Scholar] [CrossRef] [PubMed]
- Gorthi, A.; Romero, J.C.; Loranc, E.; Cao, L.; Lawrence, L.A.; Goodale, E.; Iniguez, A.B.; Bernard, X.; Masamsetti, V.P.; Roston, S.; et al. EWS-FLI1 Increases Transcription to Cause R-Loops and Block BRCA1 Repair in Ewing Sarcoma. Nature 2018, 555, 387–391. [Google Scholar] [CrossRef]
- Kannan, A.; Bhatia, K.; Branzei, D.; Gangwani, L. Combined Deficiency of Senataxin and DNA-PKcs Causes DNA Damage Accumulation and Neurodegeneration in Spinal Muscular Atrophy. Nucleic Acids Res. 2018, 46, 8326–8346. [Google Scholar] [CrossRef]
- Chen, L.; Chen, J.-Y.; Huang, Y.-J.; Gu, Y.; Qiu, J.; Qian, H.; Shao, C.; Zhang, X.; Hu, J.; Li, H.; et al. The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations. Mol. Cell 2018, 69, 412–425.e6. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.; Ahmed, D.; Dolatshad, H.; Tatwavedi, D.; Schulze, U.; Sanchi, A.; Ryley, S.; Dhir, A.; Carpenter, L.; Watt, S.M.; et al. SF3B1 Mutations Induce R-Loop Accumulation and DNA Damage in MDS and Leukemia Cells with Therapeutic Implications. Leukemia 2020, 34, 2525–2530. [Google Scholar] [CrossRef] [PubMed]
- Yankova, E.; Blackaby, W.; Albertella, M.; Rak, J.; De Braekeleer, E.; Tsagkogeorga, G.; Pilka, E.S.; Aspris, D.; Leggate, D.; Hendrick, A.G.; et al. Small Molecule Inhibition of METTL3 as a Strategy against Myeloid Leukaemia. Nature 2021, 593, 597–601. [Google Scholar] [CrossRef]
- Li, X.; Zheng, M.; Ma, S.; Nie, F.; Yin, Z.; Liang, Y.; Yan, X.; Wen, W.; Yu, J.; Liang, Y.; et al. YTHDC1 Is a Therapeutic Target for B-Cell Acute Lymphoblastic Leukemia by Attenuating DNA Damage Response through the KMT2C-H3K4me1/Me3 Epigenetic Axis. Leukemia 2025, 39, 308–322. [Google Scholar] [CrossRef]
- Vitanza, N.A.; Biery, M.C.; Myers, C.; Ferguson, E.; Zheng, Y.; Girard, E.J.; Przystal, J.M.; Park, G.; Noll, A.; Pakiam, F.; et al. Optimal Therapeutic Targeting by HDAC Inhibition in Biopsy-Derived Treatment-Naïve Diffuse Midline Glioma Models. Neuro-Oncol. 2020, 23, 376–386. [Google Scholar] [CrossRef]
- Kumar, S.; Hsiao, Y.-W.; Wong, V.H.Y.; Aubin, D.; Wang, J.-H.; Lisowski, L.; Rakoczy, E.P.; Li, F.; Alarcon-Martinez, L.; Gonzalez-Cordero, A.; et al. Characterization of RNA Editing and Gene Therapy with a Compact CRISPR-Cas13 in the Retina. Proc. Natl. Acad. Sci. USA 2024, 121, e2408345121. [Google Scholar] [CrossRef]
- Zhu, G.; Zhou, X.; Wen, M.; Qiao, J.; Li, G.; Yao, Y. CRISPR–Cas13: Pioneering RNA Editing for Nucleic Acid Therapeutics. Biodesign Res. 2024, 6, 0041. [Google Scholar] [CrossRef] [PubMed]
- Shi, H.; Xu, Y.; Tian, N.; Yang, M.; Liang, F.-S. Inducible and Reversible RNA N6-Methyladenosine Editing. Nat. Commun. 2022, 13, 1958. [Google Scholar] [CrossRef] [PubMed]
- Xia, Z.; Tang, M.; Ma, J.; Zhang, H.; Gimple, R.C.; Prager, B.C.; Tang, H.; Sun, C.; Liu, F.; Lin, P.; et al. Epitranscriptomic Editing of the RNA N6-Methyladenosine Modification by dCasRx Conjugated Methyltransferase and Demethylase. Nucleic Acids Res. 2021, 49, 7361–7374. [Google Scholar] [CrossRef]
- Hu, L.; Liu, S.; Peng, Y.; Ge, R.; Su, R.; Senevirathne, C.; Harada, B.T.; Dai, Q.; Wei, J.; Zhang, L.; et al. m6A RNA Modifications Are Measured at Single-Base Resolution across the Mammalian Transcriptome. Nat. Biotechnol. 2022, 40, 1210–1219. [Google Scholar] [CrossRef] [PubMed]
- Malig, M.; Chedin, F. Characterization of R-Loop Structures Using Single-Molecule R-Loop Footprinting and Sequencing. Methods Mol. Biol. 2020, 2161, 209–228. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kim, N.; Sun, H. The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability. Epigenomes 2025, 9, 21. https://doi.org/10.3390/epigenomes9020021
Kim N, Sun H. The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability. Epigenomes. 2025; 9(2):21. https://doi.org/10.3390/epigenomes9020021
Chicago/Turabian StyleKim, Nicholas, and Hong Sun. 2025. "The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability" Epigenomes 9, no. 2: 21. https://doi.org/10.3390/epigenomes9020021
APA StyleKim, N., & Sun, H. (2025). The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability. Epigenomes, 9(2), 21. https://doi.org/10.3390/epigenomes9020021