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G-quadruplex DNA: a novel target for drug design

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Abstract

G-quadruplex (G4) DNA is a type of quadruple helix structure formed by a continuous guanine-rich DNA sequence. Emerging evidence in recent years authenticated that G4 DNA structures exist both in cell-free and cellular systems, and function in different diseases, especially in various cancers, aging, neurological diseases, and have been considered novel promising targets for drug design. In this review, we summarize the detection method and the structure of G4, highlighting some non-canonical G4 DNA structures, such as G4 with a bulge, a vacancy, or a hairpin. Subsequently, the functions of G4 DNA in physiological processes are discussed, especially their regulation of DNA replication, transcription of disease-related genes (c-MYC, BCL-2, KRAS, c-KIT et al.), telomere maintenance, and epigenetic regulation. Typical G4 ligands that target promoters and telomeres for drug design are also reviewed, including ellipticine derivatives, quinoxaline analogs, telomestatin analogs, berberine derivatives, and CX-5461, which is currently in advanced phase I/II clinical trials for patients with hematologic cancer and BRCA1/2-deficient tumors. Furthermore, since the long-term stable existence of G4 DNA structures could result in genomic instability, we summarized the G4 unfolding mechanisms emerged recently by multiple G4-specific DNA helicases, such as Pif1, RecQ family helicases, FANCJ, and DHX36. This review aims to present a general overview of the field of G-quadruplex DNA that has progressed in recent years and provides potential strategies for drug design and disease treatment.

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Acknowledgements

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Funding

This work was supported by the Natural Science Foundation of China (Grant Number: 81970676), the key projects of the Sichuan Science and Technology Department (Grant Number: 2019YFS0537 and 2020YFS0456), the Research Startup Funding of the Affiliated Hospital of Southwest Medical University (Grant Number: 18102), Scientific Research Funding of Luzhou-Southwest Medical University (Grant Number: 2019LZXNYDJ06). The research was conducted within the context of the International Associated Laboratory ‘Helicase-mediated G-quadruplex DNA unwinding and Genome Stability’.

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  1. Fang-Yuan Teng and Zong-Zhe Jiang have contributed equally to this work.

Authors and Affiliations

  1. Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Fang-Yuan Teng, Zong-Zhe Jiang, Xiao-Zhen Tan, Feng Chen & Yong Xu

  2. Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Fang-Yuan Teng, Zong-Zhe Jiang, Man Guo, Xiao-Zhen Tan & Yong Xu

  3. Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, and Sichuan Clinical Research Center for Nephropathy, and Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Fang-Yuan Teng, Zong-Zhe Jiang, Man Guo, Xiao-Zhen Tan & Yong Xu

  4. State Key Laboratory of Crop Stress Biology for Arid Areas and College of Life Sciences, Northwest A&F University, Yangling, 712100, Shaanxi, China

    Fang-Yuan Teng & Xu-Guang Xi

  5. LBPA, Ecole Normale Supérieure Paris-Saclay, CNRS, Université Paris Saclay, 61, Avenue du Président Wilson, 94235, Cachan, France

    Xu-Guang Xi

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XGX and YX conceived and supervised the study and provided resources; FYT and ZZJ wrote the manuscript; FYT, MG, and XZT made the tables and created the figures; XGX, YX, and FC made manuscript revisions.

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Teng, FY., Jiang, ZZ., Guo, M. et al. G-quadruplex DNA: a novel target for drug design. Cell. Mol. Life Sci. 78, 6557–6583 (2021). https://doi.org/10.1007/s00018-021-03921-8

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