G4 DNA Helicases in Human Disease: Putative Tumor Suppressor Activity in the Context of G4-Unwinding

Abstract

Despite increasing evidence pointing toward the ubiquitous role of G4 structures in DNA metabolism, the existence of G4 nucleic acids in living cells has been disputed. For instance, while a wealth of in vitro data on these structures has been amassed, there exists a relative dearth of experimental results demonstrating the formation and function of G4 structures in vivo. However, this is beginning to change with a recent increase in number of in vivo studies. For now, good evidence, although indirect, for G4 structures in vivo exists in findings that show that G4 motifs are widely evolutionarily conserved and overrepresented in key genomic regions.

The mutation of helicases capable of resolving G-quadruplex (also known as G4) structures in humans is associated with genome instability and subsequent downstream effects such as premature aging and an increased risk of sporadic cancer. The goal of this project is to provide a broad overview of our current knowledge of G4 structures, helicases that unwind these G4 structures, and their relevance to the symptoms commonly associated with the helicases in human disease. In particular, it is currently debated whether the genomic rearrangements leading to subsequent disease phenotypes are causally linked to the deficiency in G4-resolving activity of these helicases.

Indeed, we would like to explore whether these G4 sites are causing the genomic rearrangements seen in tumors of human FANCJ, Bloom, and Werner’s patients, in other nonhereditary sporadic cancers, and in other related diseases. Currently, more than 43 tested helicases, including human FANCJ, human RECQ, and human Pif1, bind and/or unwind G4 structures in vitro. Particular focus will be allocated to the investigation of Pif1, FANCJ, RTEL, and RECQ helicases, as these human helicases have been the most extensively studied and are widely reported to be associated with human disease in the clinic. Future experiments that further investigate the causal link between G4 DNA helicases and the genomic rearrangements underlying human disease will be proposed. Historically, not many experiments have been performed with this distinguishing factor at the root of the purpose. Lastly, promising areas for the future of G4 DNA helicase research will be identified.