Put on your thinking cap: G-quadruplexes, helicases, and telomeres

that form in G-rich tracts of the genome affect chromosomal stability and processes such as copying the genetic information (DNA replication) or decoding the information (RNA transcription) has posed a significant challenge to researchers in the field. Although historically there has been some controversy over the existence of G4 DNA structures in vivo, emerging evidence suggests that they are indeed likely to form and have cellular consequences. In a recent study, Smith et al. investigated a role of G4 DNA in telomere capping [1], i.e., the adaptation of a nucleoprotein structure that prevents the chromosomal DNA ends from being recognized as DNA breaks and protects them from becoming degraded or fused. Telomere capping is a fairly complex process since a number of proteins have been shown to bind telomeric single-stranded or double-stranded DNA at the chromosome end. Moreover, the ability of telomeric DNA to form a variety of conformations including t-loops and G-quadruplexes adds to the complexity of how competing proteins and DNA structures influence the structural topology and metabolism of chromosome ends [2]. Using genetic and pharmacological approaches, Smith et al. showed that under conditions that stabilize G4 DNA structures, which form from a guanine-rich telomeric ssDNA exposed in a yeast temperature sensitive cdc13-1 mutant, telomere capping is in turn enhanced and phenotypes associated with capping defects are suppressed [1]. Conversely, telomere uncapping occurs under conditions that dissuade the formation of telomeric G4 DNA in the cdc13-1 mutant. The authors proposed a model in which G4 DNA structure enables G4 DNA binding proteins to further stabilize the telomere end by binding Commentary to G-quadruplex DNA, thereby preventing 5' to 3' exonucleolytic resection when the normal protein that blocks telomeric end processing is defective. Rad53-mediated checkpoint activation is also dampened, permitting suppression of the growth defects characteristic of the cdc13-1 mutant at the nonpermissive temperature. Collectively, the work of Smith et al. provides strong experimental evidence that G-quadruplex-based telomere capping can help the cell evade adverse biological effects of a deficiency in natural full telomere capping. Demonstration that G-quadruplex-based telomere capping occurs in vivo is not only enlightening for telomere biologists, but more generally for those interested in the relative importance placed on noncanonical DNA structures, such as G4, in cellular nucleic acid metabolism. Traditionally, it was proposed that G-quadruplexes, which form from transient single-stranded species that arise during normal cellular DNA metabolism, may impede replication or transcription, and become …