Functional Analysis of Interactions Between 53BP1, BRCA1 and p53
Abstract
53BP1 has been suggested to play a role in DNA damage recognition and/or repair. We could show that upon exposure of cells to ionizing radiation, 53BPl rapidly colocalizes with phosphorylated H2Ax (g-H2Ax) in megabase regions surrounding the sites of DNA strand breaks. The 53BP1 region required and sufficient for 53BPl foci formation lies upstream of the 53BPl C-terminus and binds to phosphorylated but not unphosphorylated H2AX in vitro. Moreover, phosphorylation of H2AX at Sl4O is critical for 53BP1 foci formation implying that a direct interaction between 53BPl and g-H2Ax is required for the accumulation of 53BPl at DNA break sites. On the other hand, radiation-induced phosophorylation of the 53BP1 N-terminus by the ATh kinase is not essential for 53BP1 foci formation and occurs independently of 53BP1 redistribution. To further investigate the physiological role of 53BPl we produced a targeted disruption of mouse 53BP1. 53BP1-deficient mice are radiation sensitive, growth retarded and immunodeficient. In addition, 53BPl-/- mice show a higher incidence of developing thymic lymphomas suggesting that 53BPl plays a role in tumor suppression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA418734
Entities
People
- Irene M. Ward
Organizations
- Mayo Clinic