Grant: Project Grant

The protein p53, also known as the guardian of the genome, is a master regulator of the response to cellular stresses. p53 is an important tumour suppressor; alterations in p53 are found in more than 50% of all cancers. We described that 53BP1 and USP28 regulate p53 for its optimal function. However, traditional approaches to studying protein function are falling short of addressing the complexity of this regulation. We recently developed precision genome editing screening to study the effect of hundreds of individual mutations in genes. Combining this approach with computational, structural and molecular biology approaches we will solve outstanding mechanistic and structural questions on the USP28-53BP1-dependent regulation of p53. Technically, these studies will exemplify the power of precision genome editing screening to solve complex biological questions inaccessible to other experimental approaches. Biologically, we will pave the path to defining the contribution of the USP28-53BP1-p53 interplay to tumorigenesis and other p53-related human disorders.