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Understanding and exploiting genome instability in cancer

Peter Stirling

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Canadian Institutes of Health Research (CIHR)
Cancer is caused by specific DNA mutations that can arise spontaneously over time. Conditions that increase DNA damage or which inhibit DNA repair can have a strong cancer-promoting effect. Old age and environmental stresses, such as exposure to radiation or carcinogenic chemicals, damage DNA and favour cancer formation. In addition, predisposing genetic factors that affect a cells' ability to protect and repair DNA promote cancer formation by causing so-called genome instability, defined as an increase in the frequency with which mutations are passed to daughter cells. Genome instability is a recognized contributor to cancer formation but can also serve as a therapeutic target by sensitizing cancer cells to treatment with DNA-damaging radiation or chemotherapies. My lab is taking a multi-level approach to understand genome instability and its application to cancer. My group has been funded to work in two broad areas over the next 5 years. First, we have received significant funds to study how alterations in a fundamental process called RNA transcription may ultimately lead to genome damage and mutations. In certain mutant cells RNA binds to genomic DNA and this hybrid DNA:RNA molecule prevents many of the normal transactions that maintain genome stability. We are studying which mutations lead to an increase in DNA:RNA hybrids, how and where those hybrids form, what is their relevance to mutant cancer cells and how can DNA:RNA hybrids, and the conditions that cause them, be exploited for cancer therapy. Second, we have received funding to study how proteins that normally respond to DNA damage are produced by cells. When a protein is made, it must fold into a three-dimensional structure and assemble with other biological molecules to perform its function. How protein folding and assembly occur for several important DNA damage response proteins is under study in our lab. These projects intersect as they describe the causes of and cellular responses to DNA damage.

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