Cellular responses to DNA damage

Background.

Gaining a better understanding of the causes and consequences of DNA damage, and the cellular systems that respond to such damage, is of huge importance for cancer research. First, DNA damage can yield mutations that promote carcinogenesis.

Second, individuals with inherited defects in certain DNA-damage response (DDR) proteins are predisposed to cancer, while somatically acquired DDR defects are key drivers of tumour evolution.

Third, besides surgery, the most widely used and efficacious cancer treatments work by generating DNA damage, with effects on cancer and normal cells yielding tumour responses and side effects, respectively.

Fourth, DDR proteins/events have potential utility as biomarkers in cancer diagnosis, prognosis, drug development and patient stratification. Finally, some DDR enzymes represent attractive targets for generating new anti-cancer agents. Aims.

By focusing on gaining a greater understanding of DDR events and associated processes in mammalian cells, the work outlined in this proposal aims to provide better insights into carcinogenesis and how it is held at bay by DDR systems. We also hope that this work will yield knowledge that can be exploited to better diagnose, monitor and/or treat cancer.

Methods.

Building on our successful previous work, we will use molecular biology, biochemical, proteomic, cell biology, chemical biology and genetic approaches to investigate DDR events, particularly those triggered by DNA double-strand breaks (DSBs).

In addition, we will harness newly developed and evolving mammalian genome engineering, DNA sequencing, cell-based genetic screening and bioinformatics methods to inform on DDR processes in normal cells and cancer cells. How this research will be used.

Our research should identify new DDR components and regulators, and will help define how these and previously known DDR proteins function mechanistically.

In particular, our work will inform on how various DSB repair proteins function and are influenced by factors such as cell-cycle status, chromatin, transcription and DNA replication, and how various protein post-translational modifications orchestrate DDR events.

Finally, with our collaborators, we will explore how our findings might suggest new therapeutic strategies for cancer and inform on how cancers evolve resistance to DNA-damaging agents and other, emerging therapies.