Document Detail


Alkylation sensitivity screens reveal a conserved cross-species functionome.
MedLine Citation:
PMID:  23038810     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To identify genes that contribute to chemotherapy resistance in glioblastoma, we conducted a synthetic lethal screen in a chemotherapy-resistant glioblastoma-derived cell line with the clinical alkylator temozolomide (TMZ) and an siRNA library tailored toward "druggable" targets. Select DNA repair genes in the screen were validated independently, confirming the DNA glycosylases uracil-DNA glycosylase (UNG) and A/G-specific adenine DNA glycosylase (MYH) as well as methylpurine-DNA glycosylase (MPG) to be involved in the response to high dose TMZ. The involvement of UNG and MYH is likely the result of a TMZ-induced burst of reactive oxygen species. We then compared the human TMZ sensitizing genes identified in our screen with those previously identified from alkylator screens conducted in Escherichia coli and Saccharomyces cerevisiae. The conserved biologic processes across all three species compose an alkylation functionome that includes many novel proteins not previously thought to impact alkylator resistance. This high-throughput screen, validation and cross-species analysis was then followed by a mechanistic analysis of two essential nodes: base excision repair (BER) DNA glycosylases (UNG, human and mag1, S. cerevisiae) and protein modification systems, including UBE3B and ICMT in human cells or pby1, lip22, stp22 and aim22 in S. cerevisiae. The conserved processes of BER and protein modification were dual targeted and yielded additive sensitization to alkylators in S. cerevisiae. In contrast, dual targeting of BER and protein modification genes in human cells did not increase sensitivity, suggesting an epistatic relationship. Importantly, these studies provide potential new targets to overcome alkylating agent resistance.
Authors:
David Svilar; Madhu Dyavaiah; Ashley R Brown; Jiang-bo Tang; Jianfeng Li; Peter R McDonald; Tong Ying Shun; Andrea Braganza; Xiao-hong Wang; Salony Maniar; Claudette M St Croix; John S Lazo; Ian F Pollack; Thomas J Begley; Robert W Sobol
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-04
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  10     ISSN:  1557-3125     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-21     Completed Date:  2013-09-03     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1580-96     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alkylation
Antineoplastic Agents, Alkylating / pharmacology*
Bacterial Proteins / genetics,  metabolism
Cell Line, Tumor
DNA Damage
DNA Glycosylases / genetics,  metabolism
DNA Repair
Dacarbazine / analogs & derivatives*,  pharmacology
Drug Resistance, Neoplasm
Escherichia coli / genetics,  metabolism
Glioblastoma / drug therapy*,  genetics*,  metabolism
Humans
N-Glycosyl Hydrolases / genetics,  metabolism
Reactive Oxygen Species / metabolism
Saccharomyces cerevisiae / genetics,  metabolism
Ubiquitin-Protein Ligases / genetics,  metabolism
Uracil-DNA Glycosidase / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA047904/CA/NCI NIH HHS; CA148629/CA/NCI NIH HHS; ES01225101/ES/NIEHS NIH HHS; ES019498/ES/NIEHS NIH HHS; GM087798/GM/NIGMS NIH HHS; P30 CA047904/CA/NCI NIH HHS; R01 CA148629/CA/NCI NIH HHS; R21 ES019498/ES/NIEHS NIH HHS; R44 GM087798/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Bacterial Proteins; 0/Reactive Oxygen Species; 7GR28W0FJI/Dacarbazine; 85622-93-1/temozolomide; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.-/N-Glycosyl Hydrolases; EC 3.2.2.-/Uracil-DNA Glycosidase; EC 3.2.2.-/adenine glycosylase; EC 6.3.2.19/UBE3B protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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