The Functional Role of the Ataxia Telangectasia Gene
Abstract
Ataxia-Telangiectasia (A-T) is an autosomal recessive disease with a complex phenotype including increased risk for cancer and radiation sensitivity. Moreover, carriers are suspected to be prone to breast cancer. We have studied the role of ATM, the product of the gene mutated in A-T. We have used cell-free system derived from Xenopus eggs to obtain novel insights on the biochemical function of ATM. We have cloned the Xenopus homologue of ATM, X-ATM and generated specific antibodies to study its function. We have described X-ATM temporal expression pattern during the cell cycle as well as its spatial distribution during development. We have shown that X-ATM is present in high molecular weight complexes. We have then demonstrated the role of X-ATM in checkpoint signaling. We have reconstituted a cell-free system that recapitulates the cellular phenotype of A-T called radio-resistant DNA synthesis (RDS) . We have shown that ATM is essential to signal following DNA double-strand breaks (DSBs) . This ATM-dependent checkpoint leads to the inhibition of DNA replication initiation. We have also established that DSBs can directly activate X-ATM protein kinase in cell-free extracts. Finally, we have analyzed the functional interactions between X-ATM and X-Mrell a protein essential for repair that displays a similar phenotype to A-T, when mutated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA405156
Entities
People
- Jean J. Gautier
Organizations
- Columbia University