Structure, Function and Chemical Biology of Nucleic Acids

Background We have established an integrated programme of fundamental research to elucidate the structure and function of nucleic acids through the application of chemical biology. Our studies have focused on alternative DNA structures, in particular G-quadruplexes that occur in genomic DNA.

This nucleic acid structural motif is implicated in processes that affect cancer biology and therefore has potential to be a molecular target for therapeutics and also serve as an indicator of cancer biology.

Aims The three main themes in the proposed programme are: Project 1 G-quadruplexes, proteins and transcription Project 2 G-quadruplexes, chromatin and epigenetic cross-talk Project 3 G-quadruplex cancer signatures, synergies and synthetic lethality The proposed programme has a particular focus on G-quadruplexes and mechanisms in transcription and chromatin regulation.

We will employ chemical approaches to map and perturb the structure and function of G-quadruplexes and their interacting proteins in the context of cellular genomes using small molecules.

These chemical biological studies will explore synthetic lethal approaches that could suggest optimal pathways for new cancer therapeutics and help to define new cancer signatures.

We will build on our recently developed approaches to apply molecular biophysics and chemical biology on a genome scale as well as cutting-edge live cell, single molecule tracking to detect the dynamics of G-quadruplexes in cells.

As part of our future work, we will also develop general approaches to better understand drug-DNA interactions in a cellular context and also in cancer disease models.

Methods We will use an integrated, interdisciplinary approach to the investigations that focus on our core strengths: a) molecular biophysics, b) small molecule-DNA interactions, c) chemical biology and d) chemistry applied to genomics.

Our programme will be augmented by closely associated collaborations involving structural biology, cell biology, cancer biology, genomics and bioinformatics with our own laboratory based at the Cancer Research UK Cambridge Institute and also with internationally leading collaborators.

How the results of this research will be used Insights from this research programme will provide an informed, mechanistic basis for pursuing G-quadruplexes as therapeutic targets in various cancers.

The results will also clarify how and the extent to which G-quadruplex signatures can be exploited for the detection, classification and treatment of cancers.