MINIREVIEW SERIES DNA G-quadruplex: structure, function and human disease Jaime Go ´ mez-Ma ´ rquez Department of Biochemistry and Molecular Biology, Faculty of Biology-CIBUS, University of Santiago de Compostela (USC), Spain The role of non-B DNA in the function and stability of genomes has become generally appreciated in recent years. It is now evident that DNA also encodes for spatial structures that are involved in gene regulation, replication and recombination. There are several types of secondary structures in non-B DNA. Among these noncanonical structures are hairpins and cruciforms, intramolecular triplexes or H-DNA, left-handed Z-DNA and guanine-rich repeats which have the capacity to adopt G-quadruplex (G4-DNA); the latter structure is also referred to in the literature as G-tetraplex. G4-DNA consists of a hydro- gen-bonded self-assembly of four guanine bases, paired by Hoogsteen bonding, which forms planar arrange- ments, the G-quartets. Charge coordination by mono- valent cations stabilizes G-quartet stacking, resulting in intramolecular or intermolecular association of four DNA strands in a parallel or antiparallel orientation. Genomes contain a high number of G-rich sequences that could form G4-DNA and this structure may serve important regulatory and structural functions; in addition, it can be the source of genomic instability which may lead to cancer, aging and human genetic dis- eases. In silico analysis using different computational methods, as well as laboratory experiments, indicates that many G-rich regions of chromosomes – rDNA, sin- gle-copy genes, recombination sites like those involved in immunoglobulin class-switching and repetitive sequences including satellite and telomeric DNA sequences – have the potential to form G4-DNA struc- tures. Interestingly, RNA is also capable of forming G4 structures even more stable than those of DNA. In this sense, it is tempting to speculate that RNA G-quadru- plexes could play a role in translation regulation, in a manner analogous to G4-DNA and transcription. In the human genome, the number of sites with the potential to form G-quadruplex is surprisingly high. Some of these sites are within genes and are potential threats to genome stability because they can alter the DNA archi- tecture and interfere with normal DNA processes, such as replication and transcription. Although G4-DNA has been rigorously studied in vitro, whether this structure actually forms in vivo and what its cellular roles might be, remains unclear. However, recent advances have made a persuasive case for the existence of G4-DNA in living cells and its par- ticipation in the regulation of processes as varied as telomere maintenance, transcription, recombination and ribosome biogenesis. This minireview series deals with the structural and functional characteristics of G4-DNA, as well as its implication in human disease. In the first minireview, Huppert gives an introduction to the structure and genomic distribution of putative G4-DNA-forming sequences and creates a theoretical background for the other two articles in the series. He discusses the com- putational approaches used to predict them on a geno- mic scale, and how the information derived can be combined with experiments to understand their biolo- gical functions. In the second minireview, Brooks, Kendrick & Hurley examine the diversity of G4 structures and i-motifs in promoter elements and attempt to categorize the differ- ent types of arrangements in which they are found. The third minireview, by Wu & Brosh, provocatively summarizes the presumed in vivo role of G4-nucleic acid structures and discusses the consequences of human genetic defects affecting the different enzymes that manipulate G-quadruplex structures. They present all the circumstantial evidence suggesting that G-quad- ruplex nucleic acid structures, which have been demon- strated unambiguously to be formed on specific sequences in naked DNA in vitro, do exist in vivo in the chromatin-embedded genomic DNA. Finally, they discuss the connections of G-quadruplexes to human genetic diseases and cancer. Jaime Go ´ mez-Ma ´ rquez is Professor of Biochemistry and Molecular Biology at the Faculty of Biology of the Univer- sity of Santiago de Compostela (USC), Spain (jaime.gomez.marquez@usc.es). In 1981, after obtaining his PhD in the biochemistry laboratory at USC, he joined the National Institutes of Health (Bethesda, MD, USA) as a postdoc- toral fellow to study the latency of HSV-1. Later, he investigated the molecular biology of prothymosin alpha and beta-thymosins. His current research focuses on analysis of the structure, phylogenetic origin and function of human minisatellite DNA. At present, he is investigating the role of G4-DNA in recombination. doi:10.1111/j.1742-4658.2010.07757.x FEBS Journal 277 (2010) 3451 ª 2010 The Author Journal compilation ª 2010 FEBS 3451 . MINIREVIEW SERIES DNA G-quadruplex: structure, function and human disease Jaime Go ´ mez-Ma ´ rquez Department of Biochemistry and Molecular Biology,. analysis of the structure, phylogenetic origin and function of human minisatellite DNA. At present, he is investigating the role of G4 -DNA in recombination. doi:10.1111/j.1742-4658.2010.07757.x FEBS