The Functional Role of the Ataxia Telangiectasia Gene
Abstract
Ataxia Telangiectasia (A-T) is an autosomal recessive disease characterized by a progressive cerebellar ataxia, severe immune deficiencies, gonadal atrophy, telangiectases, increased risk for cancer, particularly lymphomas, and radiation sensitivity. Additionally, carriers are suspected to be prone to other cancers including breast cancer. We are studying the biochemical function of ATM the product of the gene mutated in A-T in Xenopus, a simple model system suitable for cell cycle and checkpoint studies. We have previously cloned Xenopus ATM (X-ATM), and characterized the protein. We have described the pattern of expression of both X-ATM mRNA and protein throughout early development in Xenopus, a model system for vertebrate development. We have established a cell-free system derived from Xenopus extracts that recapitulates A DNA damage checkpoint in vitro. Under these conditions, we have demonstrated that double strand breaks (DSBs), the most harmful type of DNA damage can activate a checkpoint. The checkpoint is ATM-dependent and leads to the inactivation of cdk2 by phosphorylation on tyrosine 15. Inhibition of cdk2 prevents the loading of cdc45 on the origin of replication, thus inhibiting initiation of DNA replication. We also demonstrated that the checkpoint is independent of p53 activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA387765
Entities
People
- Jean Gautier
Organizations
- Columbia University