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Blood
2008 Aug 15;1124:1413-23. doi: 10.1182/blood-2007-07-104257.
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Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks.
Sallmyr A
,
Tomkinson AE
,
Rassool FV
.
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Expression of oncogenic BCR-ABL in chronic myeloid leukemia (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 nonhomologous 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 IIIalpha, and the protein deleted in Werner syndrome, WRN, are up-regulated. DNA ligase IIIalpha and WRN form a complex that is recruited to DSBs in CML cells. Furthermore, "knockdown" of either DNA ligase IIIalpha or WRN leads to increased accumulation of unrepaired DSBs, 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 IIIalpha and WRN. We suggest that, although the repair of ROS-induced DSBs by this pathway contributes to the survival of CML cells, the resultant genomic instability drives disease progression.
Bachrati,
RecQ helicases: suppressors of tumorigenesis and premature aging.
2003, Pubmed
Bachrati,
RecQ helicases: suppressors of tumorigenesis and premature aging.
2003,
Pubmed
Brady,
Increased error-prone NHEJ activity in myeloid leukemias is associated with DNA damage at sites that recruit key nonhomologous end-joining proteins.
2003,
Pubmed
Cheng,
Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution.
2003,
Pubmed
Cooper,
Ku complex interacts with and stimulates the Werner protein.
2000,
Pubmed
Corneo,
Rag mutations reveal robust alternative end joining.
2007,
Pubmed
Deutsch,
BCR-ABL down-regulates the DNA repair protein DNA-PKcs.
2001,
Pubmed
Difilippantonio,
DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.
2000,
Pubmed
Druker,
Chronic myelogenous leukemia.
2001,
Pubmed
Falzon,
EBP-80, a transcription factor closely resembling the human autoantigen Ku, recognizes single- to double-strand transitions in DNA.
1993,
Pubmed
Gaymes,
Increased error-prone non homologous DNA end-joining--a proposed mechanism of chromosomal instability in Bloom's syndrome.
2002,
Pubmed
Gaymes,
Myeloid leukemias have increased activity of the nonhomologous end-joining pathway and concomitant DNA misrepair that is dependent on the Ku70/86 heterodimer.
2002,
Pubmed
Göttlich,
Rejoining of DNA double-strand breaks in vitro by single-strand annealing.
1998,
Pubmed
,
Xenbase
Gottlieb,
The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen.
1993,
Pubmed
Grawunder,
Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells.
1997,
Pubmed
Hickson,
RecQ helicases: caretakers of the genome.
2003,
Pubmed
Jeggo,
Artemis links ATM to double strand break rejoining.
2005,
Pubmed
Kantarjian,
Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure.
2007,
Pubmed
Karmakar,
Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus.
2002,
Pubmed
Klassen,
Homologous recombination and the yKu70/80 complex exert opposite roles in resistance against the killer toxin from Pichia acaciae.
2007,
Pubmed
Li,
Displacement of DNA-PKcs from DNA ends by the Werner syndrome protein.
2002,
Pubmed
Li,
Functional interaction between Ku and the werner syndrome protein in DNA end processing.
2000,
Pubmed
Li,
Requirements for the nucleolytic processing of DNA ends by the Werner syndrome protein-Ku70/80 complex.
2001,
Pubmed
Liang,
Homology-directed repair is a major double-strand break repair pathway in mammalian cells.
1998,
Pubmed
Majsterek,
Does the bcr/abl-mediated increase in the efficacy of DNA repair play a role in the drug resistance of cancer cells?
2002,
Pubmed
Mari,
Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4.
2006,
Pubmed
Mimori,
Mechanism of interaction between Ku protein and DNA.
1986,
Pubmed
Mohaghegh,
The Bloom's and Werner's syndrome proteins are DNA structure-specific helicases.
2001,
Pubmed
Nowicki,
BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks.
2004,
Pubmed
Orren,
A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA.
2001,
Pubmed
Oshima,
Lack of WRN results in extensive deletion at nonhomologous joining ends.
2002,
Pubmed
Paull,
A mechanistic basis for Mre11-directed DNA joining at microhomologies.
2000,
Pubmed
Perry,
WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing.
2006,
Pubmed
Rassool,
Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2.
1996,
Pubmed
Rassool,
Constitutive DNA damage is linked to DNA replication abnormalities in Bloom's syndrome cells.
2003,
Pubmed
Riballo,
Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient.
1999,
Pubmed
Richardson,
Coupled homologous and nonhomologous repair of a double-strand break preserves genomic integrity in mammalian cells.
2000,
Pubmed
Roth,
Mechanisms of nonhomologous recombination in mammalian cells.
1985,
Pubmed
Roth,
Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction.
1986,
Pubmed
Sattler,
The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells.
2000,
Pubmed
Sawyers,
Signal transduction pathways involved in BCR-ABL transformation.
1997,
Pubmed
Skorski,
BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability.
2002,
Pubmed
Slupianek,
Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis.
2002,
Pubmed
Tomkinson,
DNA ligases: structure, reaction mechanism, and function.
2006,
Pubmed
Wang,
PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways.
2006,
Pubmed
Wang,
DNA ligase III as a candidate component of backup pathways of nonhomologous end joining.
2005,
Pubmed
Wang,
Biochemical evidence for Ku-independent backup pathways of NHEJ.
2003,
Pubmed
Yan,
IgH class switching and translocations use a robust non-classical end-joining pathway.
2007,
Pubmed
Zhang,
Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination.
2007,
Pubmed
