The genome of a cell is continually damaged by chemicals, radiation and free radicals, which results in changes to the chemical structure of DNA. Double-strand breaks stand out as the most toxic form of DNA damage, and can result in genome rearrangements and cell death if not repaired correctly. Somewhat paradoxically, many cancer treatments (chemotherapy and radiation) intentionally cause DNA double-strand breaks to kill cancer cells.
Matthew J. Schellenberg, Ph.D., uses structural biology coupled with cellular biology to develop molecular models of DNA repair components and uncover the molecular determinants of radiation and chemotherapy response.
- Structural biology. Dr. Schellenberg uses structural biology (X-ray crystallography, small-angle X-ray scattering and cryo-EM) to determine the 3D structure of proteins and protein complexes that identify and reverse DNA damage. Structural models inform us of how protein molecules function, and how drugs that bind to them exert their effect.
- DNA damage response. Human cells repair DNA damage using a collection of proteins known as DNA damage response. Dr. Schellenberg aims to determine how DNA damage response proteins function, and how they can lead to positive and negative outcomes in cancer biology.
- DNA-protein crosslinks. A major class of chemotherapeutics hijacks a cellular enzyme called Topoisomerase 2, and cause it to generate double-strand DNA breaks with protein blocked ends. This complex type of DNA damage is called a Topoisomerase 2 DNA-protein crosslink, and it can effectively kill cancer cells. Dr. Schellenberg is determining how cells repair this lesion and can become resistant to chemotherapy.
- Failed repair and DNA translocations. Incorrect repair of DNA double-strand breaks can join the wrong DNA ends together, and cause DNA translocations. Erroneous Topoisomerase 2 DNA-protein crosslink repair can yield translocations that cause pediatric cancers as well as leukemias associated with certain chemotherapy regimens. Dr. Schellenberg aims to determine the mechanisms that lead to these negative outcomes.
- In vitro assays to evaluate repair capacity of tumors. Dr. Schellenberg uses the latest techniques in recombinant protein expression and biological chemistry to make synthetic version of complex DNA lesions. These reagents are used to find new DNA repair activities associated with individual proteins or cellular extract. Dr. Schellenberg's hope is that these reagents can be used to evaluate the repair capacity of tumors so drug efficacy can be evaluated prior to treatment.
Significance to patient care
DNA damage response proteins protect the integrity of the genome and impact cancer in two important ways: They protect our cells from accumulating the mutations that cause cancer and they also cause resistance to the radiation and chemotherapy used to treat cancer. Dr. Schellenberg's research aims to determine how cells identify DNA lesions and promote effective DNA repair. This will lead to a better understanding of how cancer-causing mutations occur, as well as how to better utilize existing cancer treatments and develop new treatments.