Title: Investigating the contribution of chromatin dynamics to DNA damage responses and genome stability
Funder: Cancer Research UK

Abstract: Background Genetic instability is a driving force during tumourigenesis. It is therefore of great importance to understand the molecular mechanisms by which cells detect and respond to threats to genome integrity. The chromatin environment is known to play an integral part of maintaining genome stability. Notably, genes encoding chromatin regulators are among the most frequently mutated in cancer, underscoring their fundamental importance to cancer biology. Work from our lab demonstrates that two chromatin remodelling complexes – SWI/SNF and INO80 – are involved in the cellular response to DNA damage and play multiple roles to promote genome stability. The epigenetic program can both regulate and be regulated by multiple cellular pathways. Consequently, it is imperative to consider these pathways when exploring the impact of chromatin regulators on genome stability. The metabolic state of the cell, which is altered in cancer cells, will influence the epigenetic landscape of the cell. Additionally, mutations in chromatin regulators are found together with other genetic changes in cancer. These changes can also influence the epigenetic landscape and DNA damage responses. An outstanding question in the field is how the metabolic state and the mutational profile influence the functions of chromatin regulators such as SWI/SNF and INO80 in maintaining genome stability. Aims and Methods Here, we propose to investigate the interplay between chromatin biology and genome stability within the framework of two aims: 1) To understand the molecular mechanisms of SWI/SNF and INO80 functions at DNA double strand breaks 2) To understand the impact of the metabolic environment and genetic context on the role of SWI/SNF and epigenetic regulators in maintaining genome stability How the results of this research will be used Unravelling the complexity of chromatin remodelling complexes and their roles in multiple cellular pathways that contribute to genome stability is a major challenge in the field. The inclusion of metabolic and genetic context in our studies is a critical step forward in addressing this complexity. These studies will contribute to the field by providing a deeper mechanistic understanding of the SWI/SNF and INO80 chromatin remodellers in DNA damage responses. They will also demonstrate how metabolic changes in cancer cells can impact on genome stability through regulation of the chromatin environment. And finally, they will provide insights into the functional relationship between SWI/SNF loss and other cancer-associated mutations. Consequently, this work will have immediate relevance to cancer biology.

Lay abstract: Background Genetic instability is a driving force during tumourigenesis. It is therefore of great importance to understand the molecular mechanisms by which cells detect and respond to threats to genome integrity. The chromatin environment is known to play an integral part of maintaining genome stability. Notably, genes encoding chromatin regulators are among the most frequently mutated in cancer, underscoring their fundamental importance to cancer biology. Work from our lab demonstrates that two chromatin remodelling complexes – SWI/SNF and INO80 – are involved in the cellular response to DNA damage and play multiple roles to promote genome stability. The epigenetic program can both regulate and be regulated by multiple cellular pathways. Consequently, it is imperative to consider these pathways when exploring the impact of chromatin regulators on genome stability. The metabolic state of the cell, which is altered in cancer cells, will influence the epigenetic landscape of the cell. Additionally, mutations in chromatin regulators are found together with other genetic changes in cancer. These changes can also influence the epigenetic landscape and DNA damage responses. An outstanding question in the field is how the metabolic state and the mutational profile influence the functions of chromatin regulators such as SWI/SNF and INO80 in maintaining genome stability. Aims and Methods Here, we propose to investigate the interplay between chromatin biology and genome stability within the framework of two aims: 1) To understand the molecular mechanisms of SWI/SNF and INO80 functions at DNA double strand breaks 2) To understand the impact of the metabolic environment and genetic context on the role of SWI/SNF and epigenetic regulators in maintaining genome stability How the results of this research will be used Unravelling the complexity of chromatin remodelling complexes and their roles in multiple cellular pathways that contribute to genome stability is a major challenge in the field. The inclusion of metabolic and genetic context in our studies is a critical step forward in addressing this complexity. These studies will contribute to the field by providing a deeper mechanistic understanding of the SWI/SNF and INO80 chromatin remodellers in DNA damage responses. They will also demonstrate how metabolic changes in cancer cells can impact on genome stability through regulation of the chromatin environment. And finally, they will provide insights into the functional relationship between SWI/SNF loss and other cancer-associated mutations. Consequently, this work will have immediate relevance to cancer biology.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE