Genome Stability

Overview

Cancers occur when mutant cells proliferate uncontrollably. Importantly these cancer cell populations are frequently heterogeneous; the cells can mutate rapidly and are then selected to survive (clonal selection). This is particularly important in breast cancer where many tumours initially respond well to drugs but frequently evolve to acquire drug resistance.

In human cells DNA is packaged with proteins to form a chromatin fibre. This serves two key purposes: first to protect the DNA from damage and second to help regulate the expression of genes.  The DNA is folded into chromatin by wrapping it around protein complexes known as nucleosomes, these then fold up in a solenoid-like structure and this solenoid is further folded to a higher-order structure.  In mammalian cells the chromatin fibre is frequently decorated with “epigenetic” modifications that can mark the transcriptional state of genes.

Gene expression is controlled at a number of levels including the conformation of the chromatin fibre and the presence or absence of epigenetic marks.  Heterogeneity in the tumour cell population can then arise by individual cells expressing a different repertoire of proteins and this might be promoted by individual cells having an unstable chromatin structure or poor control of the regulatory epigenetic marks.

Our Focus

The packaging of DNA in cells into chromatin is a highly organised process and the folding of the chromatin fibre will have an influence on the expression of many genes. We are investigating genomic instability at two fundamental levels. Firstly we are interested in the relationship between higher-order chromatin fibre packaging and transcription and secondly we are studying protein complexes that are recruited to the chromatin fibre to epigenetically decorate genes to mark their transcriptional state. If these processes occur aberrantly the transcriptional competence of the genome will be changed, the cell population will become heterogeneous facilitating tumour evolution.  A better understanding of the processes that control gene transcription will provide new strategies for the development of novel drugs aimed at reducing the propensity for cells to undergo a change in genome stability. In turn this will enable us to reduce the likelihood of cells evolving to become drug resistant and evade cell death.