Zhang, DongZaugg, KathrinMak, Tak W.Elledge, Stephen2019-08-192006-08Zhang, Dong, Kathrin Zaugg, Tak W. Mak, and Stephen J. Elledge. 2006. “A Role for the Deubiquitinating Enzyme USP28 in Control of the DNA-Damage Response.” Cell 126 (3): 529–42. https://doi.org/10.1016/j.cell.2006.06.039.0092-8674http://nrs.harvard.edu/urn-3:HUL.InstRepos:41200911The Chk2-p53-PUMA pathway is a major regulator of DNA-damage-induced apoptosis in response to double-strand breaks in vivo. Through analysis of 5313131 complexes we have discovered a new ubiquitin protease, USP28, which regulates this pathway. Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 5313131 in response to DNA damage. In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA. Our studies implicate DNA-damage-induced ubiquitination and deubiquitination as a major regulator of the DNA-damage response for Chk2, 5313131, and a number of other proteins in the DNA-damage checkpoint pathway, including several mediators, such as Mdc1, Claspin, and TopBP1.en-USJournal Article2019-08-1910.1016/j.cell.2006.06.039