1. ¹Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
2. ²Howard Hughes Medical Institute and Department of Molecular Genetics, Biochemistry, and Microbiology, The University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA

Correspondence: T Skorski or A Slupianek, Center of Biotechnology, College of Science and Technology, Temple University, Bio-Life Sciences Building, Room 419 (TS) or 413 (AS), 1900 N. 12th Street, Philadelphia, PA 19122, USA. E-mail: tomasz.skorski@temple.edu or aslupian@temple.edu

Received 11 November 2004; Revised 12 January 2005; Accepted 12 January 2005; Published online 7 March 2005.

Abstract

Bloom protein (BLM) is a 3'–5' helicase, mutated in Bloom syndrome, which plays an important role in response to DNA double-strand breaks and stalled replication forks. Here, we show that BCR/ABL tyrosine kinase, which also modulates DNA repair capacity, is associated with elevated expression of BLM. Downregulation of BLM by antisense cDNA or dominant-negative mutant inhibits homologous recombination repair (HRR) and increases sensitivity to cisplatin in BCR/ABL-positive cells. Bone marrow cells from mice heterozygous for BLM mutation, BLM^Cin/+, transfected with BCR/ABL display increased sensitivity to cisplatin compared to those obtained from the wild-type littermates. BCR/ABL promotes interactions of BLM with RAD51, while simultaneous overexpression of BLM and RAD51 in normal cells increases drug resistance. These data suggest that BLM collaborates with RAD51 to facilitate HRR and promotes the resistance of BCR/ABL-positive leukemia cells to DNA-damaging agents.