Document Detail


The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage.
MedLine Citation:
PMID:  20663905     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Frances J Mao; Julia M Sidorova; Julia M Lauper; Mary J Emond; Raymond J Monnat
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-07-27
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-16     Completed Date:  2010-11-10     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6548-55     Citation Subset:  IM    
Copyright Information:
(c)2010 AACR.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / 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:
P01 CA077852-11A1/CA/NCI NIH HHS; P01 CA77852/CA/NCI NIH HHS; T32 CA080416/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/H2AFX protein, human; 0/Histones; EC 3.1.-/Exodeoxyribonucleases; EC 3.6.1.-/Bloom syndrome protein; EC 3.6.1.-/WRN protein, human; EC 3.6.4.12/RecQ Helicases; G34N38R2N1/Bromodeoxyuridine; Q20Q21Q62J/Cisplatin; U3P01618RT/Fluorouracil; X6Q56QN5QC/Hydroxyurea; XT3Z54Z28A/Camptothecin
Comments/Corrections

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