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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1413-1423. Prepublished online as a Blood First Edition Paper on June 4, 2008; DOI 10.1182/blood-2007-07-104257. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2007-07-104257v1 112/4/1413    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sallmyr, A. Articles by Rassool, F. V Search for Related Content PubMed PubMed Citation Articles by Sallmyr, A. Articles by Rassool, F. V Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 30, 2007 Accepted May 17, 2008 Up-regulation of WRN and DNA ligase III in chronic myeloid leukemia: consequences for the repair of DNA double strand breaks Annahita Sallmyr, Alan E Tomkinson, and Feyruz V Rassool* Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States * Corresponding author; email: frassool{at}som.umaryland.edu. Expression of oncogenic BCR-ABL in CML results in increased reactive oxygen species (ROS) that in turn cause increased DNA damage, including DNA double strand breaks (DSBs). We have previously shown increased error-prone repair of DSBs by non homologous end-joining (NHEJ), in CML cells. Recent reports have identified alternative NHEJ pathways that are highly error-prone prompting us to examine the role of the alternative NHEJ pathways in BCR-ABL-positive CML. Importantly, we show that key proteins in the major NHEJ pathway, Artemis and DNA ligase IV, are down-regulated whereas DNA ligase III, and the protein deleted in Werner's syndrome, WRN, are up-regulated. DNA ligase III and WRN form a novel complex that is recruited to DSBs in CML cells. Furthermore, "knockdown" of either DNA ligase III or WRN leads to increased accumulation of unrepaired DSB, demonstrating that they contribute to the repair of DSBs. These results indicate that altered DSB repair in CML cells is caused by the increased activity of an alternative NHEJ repair pathway, involving DNA ligase III and WRN. We suggest that, while the repair of ROS-induced DSBs by this pathway contributes to the survival of CML cells, the resultant genomic instability drives disease progression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. S. Fernandes, M. M. Reddy, J. R. Gonneville, S. C. DeRoo, K. Podar, J. D. Griffin, D. M. Weinstock, and M. Sattler BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair Blood, August 27, 2009; 114(9): 1813 - 1819. [Abstract] [Full Text] [PDF] A. Kotnis, L. Du, C. Liu, S. W Popov, and Q. Pan-Hammarstrom Non-homologous end joining in class switch recombination: the beginning of the end Phil Trans R Soc B, March 12, 2009; 364(1517): 653 - 665. [Abstract] [Full Text] [PDF] S. Iiizumi, A. Kurosawa, S. So, Y. Ishii, Y. Chikaraishi, A. Ishii, H. Koyama, and N. Adachi Impact of non-homologous end-joining deficiency on random and targeted DNA integration: implications for gene targeting Nucleic Acids Res., November 1, 2008; 36(19): 6333 - 6342. [Abstract] [Full Text] [PDF]

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