The Structure and Function of DNA G-Quadruplexes

Abstract

Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery.

Highlights

• Endogenous DNA G-quadruplex (G4) structures have been detected in human cells and mapped in genomic DNA and in an endogenous chromatin context by adapting next-generation sequencing approaches, to reveal cell type- and cell state-specific G4 landscapes and a strong link of G4s with elevated transcription. Synthetic small molecules and engineered antibodies have been vital to probe G4 existence and functions in cells.

• Several endogenous proteins have been found to interact with DNA G4s, including helicases, transcription factors, and epigenetic and chromatin remodellers. Detailed structural and functional studies provided novel insight into G4–protein interactions and revealed a potential involvement of G4s in a range of biological processes.

• Multiple new lines of evidence suggest that G4s play a role in cancer growth and progression. More G4s are detectable in cancer cell states compared with normal state, rendering G4s highly interesting targets in drug discovery. Recent studies have started to explore the potential for synthetic lethality and global modulation of cancer gene transcription.