Exploring the Kinome for DNA Repair and Cancer Regulatory Pathways
Barry Sleckman, WCM
Marcus Smolka, Cornell University
Cancer cells have unstable genomes with alterations, such as chromosomal translocations and deletions, often leading to cellular changes that improve cancer cell fitness, allowing tumors to be more aggressive and resistant to therapy. These alterations frequently arise from the misrepair of DNA double strand breaks (DSBs), which are normally repaired by highly conserved and efficient cellular pathways. These pathways are regulated by kinases, enzymes that add phosphate groups on to proteins, altering their functions in DNA DSB repair. There are three kinases; ATM, ATR and DNA-PKcs that play central roles in regulating DNA repair. These kinases have some overlapping functions in DNA repair and the inactivation of one, which happens in many tumors, leaves cells reliant on another to maintain genome stability. Indeed, ATM and DNA-PKcs have redundant functions in DSB repair and drugs that inhibit DNA-PKcs have therapeutic efficacy in treating ATM-deficient tumors. In addition to ATM, ATR and DNA-PKcs, it is clear that there are additional kinases that are important for regulating DNA repair and promoting genome stability in cancer cells. However, it has been difficult to identify these kinases and evaluate their activity in tumors due to their redundant functions with other kinases and cellular pathways. Here we devise an approach for identifying the full spectrum of kinases that regulate DNA DSB repair in normal and cancer cells. These studies will lay the groundwork for subsequent analyses of these kinases as therapeutic targets for treating cancer.
This represents a new collaboration between the Sleckman and Smolka laboratories. The studies are well grounded in the non-overlapping complementary expertise of both laboratories and they represent an important new unfunded research focus for both laboratories.