Non-B-DNA occurs in regions of genomic DNA that are important for cellular regulation of a number of biochemical events, particularly transcription. Regulation involving non-B-DNA appears primarily due to interactions between specific proteins and alternate DNA structures, especially when the DNA is guanine-rich. These G-rich regions preferentially cluster around the transcriptional start site throughout the genome peaking within 50 bp of the TSS, with a high prevalence in oncogenic promoters including some representatives of the hallmarks of cancer. Negative superhelicity induced by transcription can promote local unwinding of these G-rich regions of DNA, which allows for the formation G4s. G4s are made up of two or more stacked tetrads, formed by the Hoogsteen hydrogen bonding of four guanines, and are stabilized by monovalent cations, such as K+. Putative G4 forming regions have at least four runs of three or more consecutive guanines (G-tracts) separated by varying nucleotides that comprise the loop structures. The structures are classified by their loop directionality, length, and constitution. Formation of these structures in DNA modulates transcription and, in RNA, affects protein expression. The more unique, non-B-DNA, globular structure and potential to regulate the transcription of a host of oncogenes make G4s an attractive drug target for the development of anti-cancer agents. Due to varying loop lengths and composition, and number of stacked tetrads, drug design for G4 moieties is analogous to targeting a unique tertiary protein structure.
Projects:
Projects:
- Clamp-mediated stabilization of the MYC promoter G-quadruplex
- Elucidation of the structure and regulation of the kRAS promoter mid-region G-quadruplex
- G4-genome in zebrafish, and regulation during embryonic development
- Role of physiologically relevant stressors - chemical and physical - in G-quadruplex formation ex vivo and in vivo
- Other:
- Targeting the ADAM-15 promoter G-quadruplex
- Role of SNP formation in G-quadruplex regulation
- Stabilization of the nRAS mRNA G-quadruplex
- Targeting the p53 intron 3 G-quadruplex for splice variation control