G-quadruplex (G4)-driven epigenomic aging

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Nucleic acid sequences rich in guanine are capable of forming four-stranded structures called G-quadruplexes(G4), stabilized by hydrogen bonding between a tetrad of guanine bases[1] and it generally extends over the C-rich strand forming a 3′ overhang reaching approximately 50–300 nucleotides in mammals.[2] Endogenous G4 (eG4), with its unique secondary structure, is involved in a variety of important biological processes such as gene transcription, translation regulation, telomere extension, and chromatin modification. [3]

The structures of eG4s are affected by interacting proteins in vivo. During DNA replication, double-stranded (dsDNA) is unwound into single-stranded DNA (ssDNA) by helicases[4] and stabilized by ssDNA-binding proteins. During transcription, the promoter TATA box interacts with TFIIH to melt the promoter. As a kind of nucleic acid structures, eG4s will inevitably be regulated by interacting proteins. The proteins that can interact with eG4s can be divided into two types according to their functions: one is the protein that can unfold eG4s (such as G4 helicase), and the other is the protein that can bind and stabilize eG4s. These two types of proteins together regulate the dynamics of eG4s in vivo.[3]

Transcription of the C-rich telomeric strand generates a class of telomeric repeat-containing RNAs called TERRA (TElomere Repeat-containing RNA) with distinct subtelomeric sequences at their 5′ end and the same G-rich telomeric sequence at their 3′ end. These features are shared by TERRA molecules expressed by all the organisms studied to date.[5] Recent evidence indicates that aging is a condition which results in upregulation of TERRA in different cellular settings.[6][7] The G-quadruplex structure of TERRA is an important recognition element for the TRF2 shelterin subunit and physically interacts with it to bind to telomeric DNA and also with TRF1 to preserve the telomere’s structural stability.[8][9]

The formation of telomeric quadruplexes has been shown to decrease the activity of the enzyme telomerase, which is responsible for elongating telomeres.[10][11][12]



High occurrences of oxidized guanines in G4 structures due to the oxidative stress occurring under the influence of the reactive oxygen species (ROS) affects the genome stability and promotes mutagenesis, that can destabilize the stacking of guanin, senescence, and other age-related diseases.[13][14] G4s in CDS (the coding sequence, that codes for a protein) and CpG regions (that contain several CpG methylated sequences of DNA) are the least likely regions to be affected by mutations, while enhancers and intergenic G4s are prone to higher variant-induced stabilization and destabilization due to the single-nucleotide variants.[15]

Small molecules targeting G4

Small molecules targeting G-quadruplexes are also important as potent drugs for therapy of cancer and other diseases.[16][17][18][19][20][21][22][23][24][25][26][27][28][29]



[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40]

G4 may participate in non-genetic mechanisms driving aging

G4s accumulate at specific genomic loci during aging and the coefficient of variation of the G4 signal increased with cell age.[41] This G4 accumulation drives clock-like chromatin opening, since G4 formation drives aging-associated, clock like chromatin opening.[41] It was shown that delayed genome replication is a general feature of aging loci and that G4 stimulates local transcription replication interaction to delay genome replication.[41] The authors of the article also hypothesized that G4 stability might also regulate age-associated DNA hypomethylation.[41] The authors also suggest that "perturbing G4 formation might be of particular interest for modulating natural and pathological aging".[41]

References

  1. ↑ Sen D, Gilbert W (1988). Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature. 334 (6180): 364–6. Bibcode:1988Natur.334..364S. doi:10.1038/334364a0. PMID 3393228
  2. ↑ Chai, W., Du, Q., Shay, J. W., & Wright, W. E. (2006). Human telomeres have different overhang sizes at leading versus lagging strands. Molecular cell, 21(3), 427-435. PMID: 16455497 DOI: 10.1016/j.molcel.2005.12.004
  3. ↑ 3.0 3.1 Zhang, Z. H., Qian, S. H., Wei, D., & Chen, Z. X. (2023). In vivo dynamics and regulation of DNA G-quadruplex structures in mammals. Cell & Bioscience, 13(1), 117. PMID: 37381029 PMC10303365 DOI: 10.1186/s13578-023-01074-8
  4. ↑ Mendoza, O., Bourdoncle, A., Boulé, J. B., Brosh Jr, R. M., & Mergny, J. L. (2016). G-quadruplexes and helicases. Nucleic acids research, 44(5), 1989-2006.
  5. ↑ Barral, A., & Déjardin, J. (2020). Telomeric chromatin and TERRA. Journal of molecular biology, 432(15), 4244-4256. PMID: 32151584 DOI: 10.1016/j.jmb.2020.03.003
  6. ↑ Rivosecchi, J., & Cusanelli, E. (2023). TERRA beyond cancer: the biology of telomeric repeat‐containing RNAs in somatic and germ cells. Frontiers in Aging, 4. PMID: 37636218 PMC10448526 DOI: 10.3389/fragi.2023.1224225
  7. ↑ Canale, P., Campolo, J., Borghini, A., & Andreassi, M. G. (2023). Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease. Biomedicines, 11(12), 3211. PMID: 38137431 PMC10740775 DOI: 10.3390/biomedicines11123211
  8. ↑ Abreu, P. L., Lee, Y. W., & Azzalin, C. M. (2022). In Vitro Characterization of the Physical Interactions between the Long Noncoding RNA TERRA and the Telomeric Proteins TRF1 and TRF2. International Journal of Molecular Sciences, 23(18), 10463. PMID: 36142374 PMC9500956 DOI: 10.3390/ijms231810463
  9. ↑ Rivosecchi, J., Jurikova, K., & Cusanelli, E. (2024). Telomere-specific regulation of TERRA and its impact on telomere stability. In Seminars in Cell & Developmental Biology (Vol. 157, pp. 3-23). Academic Press.
  10. ↑ De Cian, A., Cristofari, G., Reichenbach, P., De Lemos, E., Monchaud, D., Teulade-Fichou, M. P., ... & Mergny, J. L. (2007). Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action. Proceedings of the National Academy of Sciences, 104(44), 17347-17352.
  11. ↑ Fletcher, T. M., Sun, D., Salazar, M., & Hurley, L. H. (1998). Effect of DNA secondary structure on human telomerase activity. Biochemistry, 37(16), 5536-5541. PMID: 9548937 DOI: 10.1021/bi972681p
  12. ↑ Bryan, T. M. (2020). G-quadruplexes at telomeres: friend or foe?. Molecules, 25(16), 3686. PMID: 32823549 PMC7464828 DOI: 10.3390/molecules25163686
  13. ↑ Bielskutė, S., Plavec, J., & Podbevšek, P. (2019). Impact of oxidative lesions on the human telomeric G-quadruplex. Journal of the American Chemical Society, 141(6), 2594-2603. PMID: 30657306 PMC6727377 DOI: 10.1021/jacs.8b12748
  14. ↑ Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., ... & Abete, P. (2018). Oxidative stress, aging, and diseases. Clinical interventions in aging, 757-772. PMID: 29731617 PMC5927356 DOI: 10.2147/CIA.S158513
  15. ↑ Neupane, A., Chariker, J. H., & Rouchka, E. C. (2023). Analysis of nucleotide variations in human g-quadruplex forming regions associated with disease states. Genes, 14(12), 2125. PMID: 36778288 PMC9915501 DOI: 10.1101/2023.01.30.526341
  16. ↑ Cao, S., Su, Q., Chen, Y. H., Wang, M. L., Xu, Y., Wang, L. H., ... & Wang, Z. G. (2024). Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides. International Journal of Molecular Sciences, 25(1), 623. https://doi.org/10.3390/ijms25010623
  17. ↑ Monsen, R.C. (2023). Higher-order G-quadruplexes in promoters are untapped drug targets. Front. Chem., 11, 1211512.
  18. ↑ Wang, K.B.; Elsayed, M.S.A.; Wu, G.; et al. (2019). Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. J. Am. Chem. Soc., 141, 11059–11070.
  19. ↑ Shu, H.; Zhang, R.; Xiao, K.; et al. (2022). G-Quadruplex-Binding Proteins: Promising Targets for Drug Design. Biomolecules, 12, 648.
  20. ↑ Kosiol, N.; Juranek, S.; Brossart, P.; et al. (2021). G-quadruplexes: A promising target for cancer therapy. Mol. Cancer, 20, 40.
  21. ↑ Teng, F.Y.; Jiang, Z.Z.; Guo, M.; et al. (2021). G-quadruplex DNA: A novel target for drug design. Cell. Mol. Life Sci., 78, 6557–6583.
  22. ↑ Zou, M.; Li, J.Y.; Zhang, M.J.; et al. (2021). G-quadruplex binder pyridostatin as an effective multi-target ZIKV inhibitor. Int. J. Biol. Macromol., 190, 178–188.
  23. ↑ Hu, X.X.; Wang, S.Q.; Gan, S.Q.; et al. (2021). A Small Ligand That Selectively Binds to the G-quadruplex at the Human Vascular Endothelial Growth Factor Internal Ribosomal Entry Site and Represses the Translation. Front. Chem., 9, 781198.
  24. ↑ Miglietta, G.; Marinello, J.; Russo, M.; Capranico, G. (2019). Ligands stimulating antitumour immunity as the next G-quadruplex challenge. Mol. Cancer 2022, 21, 180.
  25. ↑ Dhamodharan, V.; Pradeepkumar, P.I. Specific Recognition of Promoter G-Quadruplex DNAs by Small Molecule Ligands and Light-up Probes. ACS Chem. Biol., 14, 2102–2114.
  26. ↑ Yang, D.; Okamoto, K. (2010). Structural Insights into G-Quadruplexes: Towards New Anticancer Drugs. Future Med. Chem., 2, 619–646.
  27. ↑ Neidle, S.; Parkinson, G. (2002). Telomere Maintenance as a Target for Anticancer Drug Discovery. Nat. Rev. Drug Discov., 1, 383–393.
  28. ↑ Sun, D.; Thompson, B.; Cathers, B.E. et al. (1997). Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound. J. Med. Chem., 40, 2113–2116.
  29. ↑ Merlino, F., Marzano, S., Zizza, P., D’Aria, F., Grasso, N., Carachino, A., ... & Pagano, B. (2024). Unlocking the potential of protein-derived peptides to target G-quadruplex DNA: from recognition to anticancer activity. Nucleic Acids Research, 52(12), 6748–6762, https://doi.org/10.1093/nar/gkae471
  30. ↑ Routh ED, Creacy SD, Beerbower PE, Akman SA, Vaughn JP, Smaldino PJ (2017). A G-quadruplex DNA-affinity Approach for Purification of Enzymaticacvly Active G4 Resolvase1. Journal of Visualized Experiments. 121 (121). doi:10.3791/55496. PMC 5409278. PMID 28362374
  31. ↑ Varshney, D., Spiegel, J., Zyner, K., Tannahill, D. & Balasubramanian, S. (2020). The regulation and functions of DNA and RNA G-quadruplexes. Nat Rev Mol Cell Biol 21, 459-474
  32. ↑ Huppert, J. L., & Balasubramanian, S. (2005). Prevalence of quadruplexes in the human genome. Nucleic acids research, 33(9), 2908-2916. PMID: 15914667 PMCID: PMC1140081 DOI: 10.1093/nar/gki609
  33. ↑ Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. (2013). Quantitative visualization of DNA G-quadruplex structures in human cells. Nat Chem 5, 182-186
  34. ↑ Hansel-Hertsch, R. et al. (2016). G-quadruplex structures mark human regulatory chromatin. Nature genetics 48, 1267-1272
  35. ↑ Hansel-Hertsch, R., Spiegel, J., Marsico, G., Tannahill, D. & Balasubramanian, S. (2018). Genome-wide mapping of endogenous G-quadruplex DNA structures by chromatin immunoprecipitation and high-throughput sequencing. Nat Protoc 13, 551-564
  36. ↑ Lyu, J., Shao, R., Kwong Yung, P. Y. & Elsasser, S. J. (2022). Genome-wide mapping of G766 quadruplex structures with CUT&Tag. Nucleic acids research 50, e13 (2022).
  37. ↑ Muller, S., Kumari, S., Rodriguez, R. & Balasubramanian, S. (2010). Small-molecule-mediated G768 quadruplex isolation from human cells. Nat Chem 2, 1095-1098
  38. ↑ Zhang, X., Spiegel, J., Martinez Cuesta, S., Adhikari, S. & Balasubramanian, S. (2021). Chemical profiling of DNA G-quadruplex-interacting proteins in live cells. Nat Chem 13, 626-633
  39. ↑ Sergeev, A. V., Loiko, A. G., Genatullina, A. I., Petrov, A. S., Kubareva, E. A., Dolinnaya, N. G., & Gromova, E. S. (2023). Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter. International Journal of Molecular Sciences, 25(1), 45. https://doi.org/10.3390/ijms25010045
  40. ↑ Soriano-Lerma, A., Sanchez-Martin, V., Murciano-Calles, J., Ortiz-Gonzalez, M., Tello-Lopez, M. J., Perez-Carrasco, V., ... & Garcia-Salcedo, J. A. (2024). Resveratrol targets G-quadruplexes to exert its pharmacological effects. bioRxiv, 2024-07. https://doi.org/10.1101/2024.07.29.605564
  41. ↑ 41.0 41.1 41.2 41.3 41.4 Jin, W., Zheng, J., Xiao, Y., Ju, L., Chen, F., Fu, J., ... & Zhang, Y. (2024). A universal molecular mechanism driving aging. bioRxiv, 2024-01. https://doi.org/10.1101/2024.01.06.574476
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