Key Points
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DNA can assume a variety of secondary structures aside from the canonical B-form. Sequences capable of forming these alternative structures in vitro are often sites of genomic instability in vivo.
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G-quadruplex (G4) DNA is a stable secondary structure held together by G-G base pairs. DNA sequences capable of forming G4 DNA in vitro (G4 motifs) are enriched in ribosomal DNA and promoter regions, and at telomeres and mitotic and meiotic double-strand break (DSB) sites. This suggests that G4 structures may form in vivo and serve one or more biological functions.
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G4 structures are predicted to form in the telomeric DNA of many species, and telomere structural proteins, such as TEBPα and TEBPβ in ciliates and Rap1 in Saccharomyces cerevisiae, promote the formation of G4 DNA in vitro. Anti-G4 DNA antibody experiments in ciliates have provided some of the best evidence to date for the existence of G4 structures in vivo.
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Genetic data suggest that G4 motifs affect the transcription of a variety of genes, most notably MYC, where the G4 motif acts as a repressor. Transcription can also be affected by binding of transcription factors to G4 structures (for example, myosin D (MyoD)), which can then titrate transcriptional regulators away from their recognition sequences in promoters.
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G4 structures must be unwound to allow faithful replication of the entire genome, a process that is likely to involve helicases. In vitro, most tested helicases can unwind G4 DNA, but PIF1 family helicases are particularly potent G4 DNA unwinders. In vivo, G4 motifs are often mutated such that they can no longer form G4 structures in the absence of certain helicases.
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Multiple lines of evidence point towards the existence of other non-B-form DNA secondary structures (such as Z-DNA, cruciforms and triplex DNA) in vivo. As with G4 DNA, these secondary structures are predicted to serve physiological functions, despite the fact that sequence motifs capable of forming Z-DNA, cruciforms or triplex DNA are mutagenic hotspots.
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Direct evidence for the existence of G4 DNA in vivo is lacking and will require novel experimental approaches to satisfy sceptics.
Abstract
In addition to the canonical double helix, DNA can fold into various other inter- and intramolecular secondary structures. Although many such structures were long thought to be in vitro artefacts, bioinformatics demonstrates that DNA sequences capable of forming these structures are conserved throughout evolution, suggesting the existence of non-B-form DNA in vivo. In addition, genes whose products promote formation or resolution of these structures are found in diverse organisms, and a growing body of work suggests that the resolution of DNA secondary structures is critical for genome integrity. This Review focuses on emerging evidence relating to the characteristics of G-quadruplex structures and the possible influence of such structures on genomic stability and cellular processes, such as transcription.
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Acknowledgements
We thank the US National Institutes of Health, the American Cancer Society and the German Research Organization (DFG) for support.
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Supplementary information S1 (table)
Helicases tested for G4 DNA binding and unwinding (PDF 103 kb)
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Glossary
- B-form DNA
-
(B-DNA). The canonical right-handed double helical secondary structure assumed by bulk DNA in vivo.
- Non-B-form secondary structures
-
Any DNA secondary structure that differs from B-form DNA. Such structures are likely to arise at defined sequence motifs owing to local factors acting on the B-form DNA.
- G-quadruplex structures
-
(G4 structures). Stable DNA secondary structures that can form from motifs containing tracts of tandem guanines. The guanines hydrogen bond in a planar arrangement, forming stacks connected by single-stranded DNA loops. The DNA strands can be parallel or antiparallel, and the G4 structures can form intra- or intermolecularly.
- Z-DNA
-
Left-handed helical DNA that can form from tracts of alternating purines and pyrimidines.
- Cruciforms
-
Four-armed DNA secondary structures, similar to Holliday junctions, that can form at inverted repeat sequences and are stabilized by DNA supercoiling.
- Triplexes
-
Three-stranded DNA in which single-stranded DNA hydrogen bonds into the major groove of purine-rich standard B-form DNA.
- Telomeres
-
The ends of linear chromosomes, usually consisting of GC-rich repeated DNA, with guanines clustered in the strand that forms the 3′ end of the chromosome. The G-rich strand is longer than the C-rich strand so that telomeres contain both double- and single-stranded DNA. Sequence-specific binding proteins protect both duplex and single-stranded telomeric DNA from degradation, fusions and checkpoints.
- Helicase
-
A class of enzymes that function as molecular motors, using the energy of ATP hydrolysis to unwind base-paired DNA or RNA. Helicases can also translocate along and displace proteins from nucleic acids.
- γH2Ax
-
A phosphorylated histone H2A variant that accumulates at regions of DNA damage.
- Telomere-dependent bouquet structure
-
A structure formed by telomeres in early meiosis. It is associated with the nuclear scaffold.
- Hoogsteen base pairing
-
Base pairing that differs from the normal Watson–Crick base pairing.
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Bochman, M., Paeschke, K. & Zakian, V. DNA secondary structures: stability and function of G-quadruplex structures. Nat Rev Genet 13, 770–780 (2012). https://doi.org/10.1038/nrg3296
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DOI: https://doi.org/10.1038/nrg3296
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