| The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage. | |
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MedLine Citation:
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PMID: 20663905 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Loss-of-function mutations in the human RecQ helicase genes WRN and BLM respectively cause the genetic instability/cancer predisposition syndromes Werner syndrome and Bloom syndrome. To identify common and unique functions of WRN and BLM, we systematically analyzed cell proliferation, cell survival, and genomic damage in isogenic cell lines depleted of WRN, BLM, or both proteins. Cell proliferation and survival were assessed before and after treatment with camptothecin, cis-diamminedichloroplatinum(II), hydroxyurea, or 5-fluorouracil. Genomic damage was assessed, before and after replication arrest, by gamma-H2AX staining, which was quantified at the single-cell level by flow cytometry. Cell proliferation was affected strongly by the extent of WRN and/or BLM depletion, and more strongly by BLM than by WRN depletion (P = 0.005). The proliferation of WRN/BLM-codepleted cells, in contrast, did not differ from BLM-depleted cells (P = 0.34). BLM-depleted and WRN/BLM-codepleted cells had comparably impaired survival after DNA damage, whereas WRN-depleted cells displayed a distinct pattern of sensitivity to DNA damage. BLM-depleted and WRN/BLM-codepleted cells had similar, significantly higher gamma-H2AX induction levels than did WRN-depleted cells. Our results provide new information on the role of WRN and BLM in determining cell proliferation, cell survival, and genomic damage after chemotherapeutic DNA damage or replication arrest. We also provide new information on functional redundancy between WRN and BLM. These results provide a strong rationale for further developing WRN and BLM as biomarkers of tumor chemotherapeutic responsiveness. |
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Authors:
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Frances J Mao; Julia M Sidorova; Julia M Lauper; Mary J Emond; Raymond J Monnat |
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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: 2010-07-27 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-16 Completed Date: 2010-11-10 Revised Date: 2011-08-16 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 6548-55 Citation Subset: IM |
Copyright Information:
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(c)2010 AACR. |
Affiliation:
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Department of Pathology, University of Washington, Seattle, Washington 98195-7705, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Bone Neoplasms / drug therapy, enzymology, genetics, pathology Bromodeoxyuridine / pharmacology Camptothecin / pharmacology Cell Growth Processes / physiology Cell Line, Tumor Cisplatin / pharmacology DNA Damage* Exodeoxyribonucleases / deficiency, metabolism* Fibroblasts / cytology, enzymology Fluorouracil / pharmacology Histones / metabolism Humans Hydroxyurea / pharmacology Osteosarcoma / drug therapy, enzymology, genetics, pathology RecQ Helicases / deficiency, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA077852-11A1/CA/NCI NIH HHS; P01 CA77852/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/H2AFX protein, human; 0/Histones; 127-07-1/Hydroxyurea; 15663-27-1/Cisplatin; 51-21-8/Fluorouracil; 59-14-3/Bromodeoxyuridine; 7689-03-4/Camptothecin; EC 3.1.-/Exodeoxyribonucleases; EC 3.6.1.-/Bloom syndrome protein; EC 3.6.1.-/RecQ Helicases; EC 3.6.1.-/WRN protein, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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