Researchers have identified novel DNA 'switches' that control the expression of genes in humans and related species1.
These switches pop up when four guanine (G) bases — G4 — club together in a G-rich DNA strand and fold back presenting a distinctly recognisable structural entity. Such strands on telomeres (chromosome ends) readily form G4 structures in vitro and possibly in vivo. However, the possibility that G4 structures may form elsewhere in the genome and influence biological function remained relatively unexplored.
With the availability of the complete genome sequence, the researchers first performed advanced bioinformatic analyses on more than 61,000 ORFs (open reading frames) in 18 prokaryotes to show enrichment of potential G4 structural switches in regulatory regions2. Extending these investigations to eukaryotes including human, chimpanzee, mouse and rat genes also revealed enriched G4s near transcription start sites.
The group had earlier demonstrated that G4s may function as gene regulatory switches in multiple cancer types. They showed that G4s are recognized and bound by a transcription factor NME2 and control expression of proto-oncogene MYC3. In addition, they used a proposed anti-cancer drug (TMPyP4, a porphyrin derivative) and measured changes in lung and cervical cancer cell transcriptomes. More than 1,100 genes changed expression; at least 700 of them contained potential G4s lending credence to importance of G4s, though it needs to be functionally established in each case.
The results suggest careful design of anti-cancer drugs which might inadvertently target promoter G4s in addition to telomeric ones causing cytotoxicity. "However, G4s in promoters of oncogenes represent specific 'druggable' targets. Advances in molecular modeling and simulations should allow for design of drugs selectively targeting 'oncogenic' G4s," says Shantanu Chowdhury, lead author from the Institute of Genomics and Integrative Biology in New Delhi.