Understanding and exploiting genome instability in cancer

Cancer is caused by specific DNA mutations that can arise spontaneously over time. Conditions that increase DNA damage or inhibit DNA repair can promote cancer. 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 double-edged sword: it can contribute to cancer formation, but it can also help with treatment by sensitizing cancer cells to anti-cancer chemotherapy or radiation treatments.

This program studies how defective RNA molecules may lead to genome instability by binding to DNA. If these hybrid DNA:RNA structures accumulate they can lead to DNA damage, increasing the chance of mutations in the DNA. Focus areas include cancer-associated mutations that lead to an increase in DNA:RNA hybrids, determining how and where those hybrids form, and how they might form the basis of new anti-cancer drugs.

The program also investigates how proteins respond to DNA damage. When a protein is made, it must fold into a three-dimensional structure and assemble with other biological molecules to perform its function. In response to DNA-damaging stress, cells can promote survival by halting this process and sequestering newly-made or damaged proteins in a regulated way. Characterizing the network of protein changes that occurs after DNA damage could help with understanding how cells cope with ongoing genome instability or treatment with chemotherapies that damage DNA.