Papers of particular interest, published within the period of

review, have been highlighted as: • of special interest We would like to thank Sam Corless for crucial comments on the manuscript and Jon Baxter for his helpful insights into DNA supercoiling in transcription and Apoptosis inhibitor replication. Research described in this review was supported by the Wellcome Trust and NG is now funded by the UK Medical Research Council. “
“Current Opinion in Genetics & Development 2014, 25:22–29 This review comes from a themed issue on Genome architecture and expression Edited by Victor Corces and David L Levens For a complete overview see the Issue and the Editorial Available online 31st December

2013 0959-437X/$ – see front matter, © 2013 The Authors. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.gde.2013.10.012 The self-assembly of guanylic acid derivatives has been known for more than a century [1] and the structural basis for this phenomenon was elucidated in the 1960s [2]. Guanine-tetrad formation Fluorouracil chemical structure (Figure 1a) drives the assembly of four-stranded helixes by guanine-rich oligonucleotides (G-quadruplexes, Figure 1b). Seminal studies by Sen and Gilbert, and by others [3, 4, 5, 6 and 7], showed that these cation-dependent, G-quadruplex structures are thermodynamically stable under physiological conditions, and subsequently such structures were proposed to be involved in telomere association, recombination and replication. Biophysical methods have provided extensive in vitro data on the structure(s) and thermodynamics of DNA G-quadruplexes formed from oligonucleotides derived from genomic sequences that have included the human telomere ( Figure 1c) [ 8] and promoter regions of oncogenes (e.g. MYC) [ 9]. Structural data

has facilitated the design and synthesis of G-quadruplex-specific small molecules [ 10] (see Figure 1d for example of G-quadruplex ligands), several of which trigger cellular mechanisms proposed to be linked with G-quadruplexes. Notable examples of chemical biological studies include the small molecule inhibition of telomerase action via G-quadruplex stabilization Phospholipase D1 [ 11], and also transcriptional suppression of MYC by a G-quadruplex ligand [ 12]. There are indeed many more examples in the literature of cell-based studies that provide supportive correlations. However, some such studies have not addressed whether the key G-quadruplex in question actually exists in the genomic DNA and if so whether it is responsible for causation of the observed effects. Biophysical studies on G-quadruplex structures formed by oligonucleotides in vitro have allowed the formulation of quadruplex-prediction algorithms on the basis of sequence motifs such as G≥3NXG≥3NXG≥3NXG≥3.