| The homologous recombination protein RAD51D mediates the processing of 6-thioguanine lesions downstream of mismatch repair. | |
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MedLine Citation:
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PMID: 21205838 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Thiopurines are extensively used as immunosuppressants and in the treatment of childhood cancers, even though there is concern about therapy-induced leukemias and myelodysplastic syndromes resulting from thiopurine use. Following metabolic activation, thiopurines are incorporated into DNA and invoke mismatch repair (MMR). Recognition of 6-thioguanine (6-thioG) in DNA by key MMR proteins results in cell death rather than repair. There are suggestions that homologous recombination (HR) is involved downstream of MMR following thiopurine treatment, but the precise role of HR is poorly understood. In this study, we demonstrate that cells deficient in RAD51D (a RAD51 paralogue) are extremely sensitive to 6-thioG. This sensitivity is almost completely rescued by the deletion of Mlh1, which suggests that HR is involved in the repair of the 6-thioG-induced recombinogenic lesions generated by MMR. Furthermore, 6-thioG induces chromosome aberrations in the Rad51d-deficient cells. Interestingly, Rad51d-deficient cells show a striking increase in the frequency of triradial and quadriradial chromosomes in response to 6-thioG therapy. The presence of these chromatid exchange-type aberrations indicates that the deficiency in RAD51D-dependent HR results in profound chromosomal damage precipitated by the processing of 6-thioG by MMR. The radials are notable as an important source of chromosomal translocations, which are the most common class of mutations found in hematologic malignancies. This study thus suggests that HR insufficiency could be a potential risk factor for the development of secondary cancers that result from long-term use of thiopurines in patients. |
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Authors:
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Preeti Rajesh; Alexandra V Litvinchuk; Douglas L Pittman; Michael D Wyatt |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-01-04 |
Journal Detail:
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Title: Molecular cancer research : MCR Volume: 9 ISSN: 1557-3125 ISO Abbreviation: Mol. Cancer Res. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-02-17 Completed Date: 2011-08-01 Revised Date: 2012-05-02 |
Medline Journal Info:
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Nlm Unique ID: 101150042 Medline TA: Mol Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 206-14 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia SC 29208, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Chromosomal Instability / drug effects DNA / metabolism DNA Damage* DNA Mismatch Repair / drug effects* DNA-Binding Proteins / deficiency, metabolism* G2 Phase / drug effects Giant Cells / drug effects, pathology Mice Recombination, Genetic / drug effects, genetics* Thioguanine / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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P20 RR17698/RR/NCRR NIH HHS; R01 CA100450/CA/NCI NIH HHS; R01 CA100450/CA/NCI NIH HHS; R01 CA100450-03/CA/NCI NIH HHS; R01 CA100450-04/CA/NCI NIH HHS; R01 CA100450-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA-Binding Proteins; 0/Rad51l3 protein, mouse; 154-42-7/Thioguanine; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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