The regulation and functions of DNA and RNA G-quadruplexes

Abstract

DNA and RNA can adopt various secondary structures. Four-stranded G-quadruplex (G4) structures form through self-recognition of guanines into stacked tetrads, and considerable biophysical and structural evidence exists for G4 formation in vitro. Computational studies and sequencing methods have revealed the prevalence of G4 sequence motifs at gene regulatory regions in various genomes, including in humans. Experiments using chemical, molecular and cell biology methods have demonstrated that G4s exist in chromatin DNA and in RNA, and have linked G4 formation with key biological processes ranging from transcription and translation to genome instability and cancer. In this Review, we first discuss the identification of G4s and evidence for their formation in cells using chemical biology, imaging and genomic technologies. We then discuss possible functions of DNA G4s and their interacting proteins, particularly in transcription, telomere biology and genome instability. Roles of RNA G4s in RNA biology, especially in translation, are also discussed. Furthermore, we consider the emerging relationships of G4s with chromatin and with RNA modifications. Finally, we discuss the connection between G4 formation and synthetic lethality in cancer cells, and recent progress towards considering G4s as therapeutic targets in human diseases.

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Fig. 1: The structure and topologies of G-quadruplexes.
Fig. 2: Approaches to detect and map DNA and RNA G-quadruplexes.
Fig. 3: Regulation of G-quadruplex structure formation.
Fig. 4: Models of G-quadruplex involvement in transcription.
Fig. 5: G-quadruplexes in RNA biology.
Fig. 6: The involvement of G-quadruplexes in epigenetic control.

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Acknowledgements

The Balasubramanian laboratory is supported by Cancer Research UK core and programme award funding (C14303/A17197; C9681/A18618), S.B. is a Senior Investigator of the Wellcome Trust (099232/Z/12/Z) and D.V. is a Herchel Smith postdoctoral fellow. J.S. gratefully acknowledges EU H2020 Framework Programme funding (H2020-MSCA-IF-2016, ID: 747297-QAPs).

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Correspondence to Shankar Balasubramanian.

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S.B. is a founder and shareholder of Cambridge Epigenetix Ltd.

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Nature Reviews Molecular Cell Biology thanks Cyril Dominguez, Sua Myong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Circular dichroism

A spectroscopic technique to investigate structure based on the interaction of plane-polarized light with a structurally asymmetric molecule.

Bayesian predictions

Statistical methods to infer probabilities for a hypothesis, which can be updated when new information becomes available.

G-fraction

The proportion of G bases in a sequence, that is, G-richness.

G-skew

The under-representation or over-representation of G bases in a sequence.

Polytene chromosomes

Giant chromosomes found in particular tissues of various eukaryotes, which are formed following several rounds of DNA replication without cell division.

Fragile telomeres

Aberrant or discontinuous appearance of telomere chromatin in metaphase chromosomes, identified by fluorescence in situ hybridization and indicative of telomere replication defects.

Common fragile sites

Specific chromosomal regions that are intrinsically hard to replicate and preferentially form chromatin gaps or breaks during metaphase following replication stress.

Stress granules

Cytoplasmic membraneless bodies of proteins and RNAs that appear in response to conditions of cellular stress.

CpG island

A genomic region with CG:GC content higher than 60%.

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Varshney, D., Spiegel, J., Zyner, K. et al. The regulation and functions of DNA and RNA G-quadruplexes. Nat Rev Mol Cell Biol (2020). https://doi.org/10.1038/s41580-020-0236-x

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