Cited by 117Chronic Myeloid Leukemia TreatmentsDNA Repair MechanismsCancer-related Molecular Pathways

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BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint

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Dierov, Jamil, Dierova, Raia, Carroll, Martin·2004·Cancer Cell

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Abstract

Chronic myelogeneous leukemia (CML) is a two-stage disease associated with expression of the BCR/ABL tyrosine kinase protein. However, whether BCR/ABL expression directly causes blast crisis, and if so by what mechanism, is unknown. We have found that BCR/ABL translocates from the cytoplasm to the nucleus after genotoxic stress. Furthermore, BCR/ABL increases DNA double-strand damage after etoposide treatment and leads to a defect in an intra-S phase checkpoint, causing a radioresistant DNA synthesis (RDS) phenotype. In the nucleus, BCR/ABL associates with the ataxia-telangiectasia and rad 3-related protein (ATR) and disrupts ATR-dependent signal transduction. Overexpression of ATR in a BCR/ABL-expressing cell line corrects the DNA damage phenotype. These results demonstrate a nuclear role for BCR/ABL in altering the cellular response to DNA damage.

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Authors: Dierov, J., Dierova, R., & Carroll, M.
Affiliations: University of Pennsylvania (US)
Corresponding author: Carroll, Martin
ORCID: Carroll, Martin
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2004-03
Volume: 5
Issue: 3
Pages: 275-285
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/s1535-6108(04)00056-x
OpenAlex: W2035713316
Cited by: 117
References: 40
Citations by year: 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 9
FWCI: 7.97
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3425 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: BCR-ABL, chronic myeloid leukemia, nuclear translocation, ATR, S-phase checkpoint, DNA damage response, radioresistant DNA synthesis, etoposide, DNA double-strand breaks, blast crisis, tyrosine kinase
MeSH terms: Cell Nucleus, Cells, Cultured, Cytoplasm, DNA Damage, DNA Topoisomerases, Type II, DNA Repair, Enzyme Inhibitors, Etoposide, Humans, Signal Transduction, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Protein Transport, Ataxia Telangiectasia Mutated Proteins

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BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint

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