Research

DNA double-strand break repair

diagram

Our research aims to understand the roles of PI3K-like kinases (ATM, ATR, and DNA-PKcs) and their downstream components in DSB sensing, signaling and repair in mammalian cells. We are examining early cellular events that occur in response to DNA breaks, with an emphasis on DNA end resection.

We find that DNA end resection by the exonuclease EXO1 is a critical step that influences the choice that a cell makes between DNA repair pathways (NHEJ vs HR) and between cell cycle checkpoint activation modes (ATM vs ATR). Research from our (and other) labs is also beginning to delineate how cyclin-dependent kinases (CDKs) regulate the choice of repair pathway by phosphorylating resection proteins – such as EXO1 in S and G2 phases of the cell cycle.

Understanding how DNA resection and repair pathways are de-regulated in cancers should provide us with exciting new opportunities for targeted cancer therapy.

DNA Repair Images
(Top) EXO1 (green) binds to and co-localizes with BRCA1 (purple) at a stripe of DNA damage (red) created with a micro-laser in a human cell nucleus (blue). (Bottom left) EXO1 knockdown attenuates resection of DNA breaks induced by ionizing radiation (IR), seen as loss of RPA foci (red). (Bottom right) EXO1 knockdown attenuates HR (error-free repair pathway) and augments NHEJ (error-prone repair pathway) resulting in radial chromosome structures (arrowhead).