The Role of Backup NHEJ Repair in Creating Genomic Instability in CML
Final rept. 1 Mar 2007-28 Feb 2008
MARYLAND UNIV BALTIMORE SCHOOL OF MEDICINE
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This proposal seeks to build on our preliminary data that provides a mechanism for the reduced repair fidelity in BCR-ABL-positive CML. In this scenario, double strand breaks DSB produced by increased reactive oxygen species ROS in BCR-ABL-positive CML need to be processed before proper repair can occur. However, we find that one key main NHEJ protein responsible for this processing, Artemis, is down-regulated in BCR-ABL-positive CML. Concomitantly, we find upregulation of a novel complex of proteins, some of which are known to be involved in a minor back-up NHEJ repair pathway. WRN, a protein, which is found deleted in the accelerated aging disease, Werners syndrome is a newly found constituent of this complex, that contains, DNA Ligase III, XRCC1 and PARP. We report that 1. The novel protein complex we have identified in CML cells localizes to DSB. 2. These proteins repair DSB because their down-regulation a increases the number of unrepaired DSB, and b affects the repair efficiency and fidelity in CML cells. Overexpression of Artemis, the main NHEJ protein found down regulated in CML cells, increases correct repair of DSB. 3. We have preliminary data that up-regulation of back-up repair proteins is dependent on expression of BCR-ABL.
- Medicine and Medical Research