Functional Analysis of Interactions Between 53BP1, BRCA1 and p53
Annual summary rept. 1 Jul 2001-30 Jun 2004
MAYO CLINIC ROCHESTER MN
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The ability to sense DNA damage and activate response pathways that coordinate cell cycle progression and DNA repair is essential for the maintenance of genomic integrity. Based on its conserved BRCT BRCA1 C-terminal domains, 53BP1 has been implicated in the DNA damage response. By studying the subcellular localization and molecular interaction of 53BP1, we could show that 53BP1 is rapidly activated in response to ionizing radiation and localizes to the sites of DNA double strand breaks. We mapped the region required for foci formation and could demonstrate that this region interacts with phoshorylated H2AX, a histone 2A variant that keeps 53BP1 in the vicinity of DNA lesions. Other interaction partners of 53BP1 include the tumor suppressor proteins p53 and BRCA1. By using a 53BP1 knock out model, we could show that 53BP1 itself acts as a tumor suppressor and that 53BP1 and p53 deficiency synergize in tumorigenesis. Furthermore, the loss of a single 53BP1 allele enhances the susceptibility to cancer in the absence of p53.
- Anatomy and Physiology
- Medicine and Medical Research