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1.
Protein J ; 30(1): 1-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21113733

ABSTRACT

The American Cancer Society's 2009 statistics estimate that 1 out of every 4 deaths is cancer related. Genomic instability is a common feature of cancerous states, and an increase in genomic instability is the diagnostic feature of Bloom Syndrome. Bloom Syndrome, a rare disorder characterized by a predisposition to cancer, is caused by mutations of the BLM gene. This study focuses on the partnerships of BLM protein to RAD51, a Homologous Recombination repair protein essential for survival. A systematic set of BLM deletion fragments were generated to refine the protein binding domains of BLM to RAD51 and determine interacting regions of BLM and ssDNA. Results show that RAD51 and ssDNA interact in overlapping regions; BLM100₋214 and BLM1317₋1367. The overlapping nature of these regions suggests a preferential binding for one partner that could function to regulate homologous recombination and therefore helps to clarify the role of BLM in maintaining genomic stability.


Subject(s)
Genomic Instability/genetics , Protein Interaction Domains and Motifs/genetics , Rad51 Recombinase/genetics , Rad51 Recombinase/metabolism , RecQ Helicases/genetics , RecQ Helicases/metabolism , Binding, Competitive , Bloom Syndrome/genetics , DNA Breaks, Double-Stranded , DNA Repair , DNA-Binding Proteins/genetics , Humans , RecQ Helicases/isolation & purification , Recombination, Genetic
2.
Mutat Res ; 673(2): 141-8, 2009 Mar 17.
Article in English | MEDLINE | ID: mdl-19429515

ABSTRACT

Arylphosphonium salts (APS) are compounds that have both lipophilic and cationic character, allowing them facile transport through plasma membranes or cell walls to accumulate in the cytoplasm or mitochondria of cells. APS molecules preferentially accumulate in tumor cells and are therefore under investigation as tumor imaging agents and mitochondrial targeting molecules. We have generated a systematic set of APS to study their ability to associate with DNA. The chemical structure of the APS determines the extent of its interaction with DNA and therefore its ability to aggregate the DNA. Also, APS compounds blocked DNA amplification in vitro at concentrations below the aggregation threshold, corroborating the structure/interaction relationship. Furthermore, the extent of APS:DNA interaction strongly correlates with bacterial toxicity, implying that APS molecules may deter cellular metabolic DNA pathways. Finally, DNA repair deficient and DNA bypass polymerase deficient bacterial strains were screened for sensitivity to APS. Interestingly, no single pathway for the repair or tolerance of these compounds was solely responsible for APS mediated toxicity. Taken together, these findings suggest that APS compounds may be capable of targeting and regulating unchecked cell growth and therefore show potential applications as a chemotherapeutic agent.


Subject(s)
DNA, Bacterial/metabolism , Organophosphorus Compounds/metabolism , Organophosphorus Compounds/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Cations/pharmacology , DNA/drug effects , DNA/metabolism , DNA, Bacterial/drug effects , Dose-Response Relationship, Drug , Escherichia coli/drug effects , Escherichia coli/genetics , Gene Amplification/drug effects , Microbial Sensitivity Tests , Microbial Viability/drug effects , Models, Biological , Molecular Conformation , Organophosphorus Compounds/chemistry , Reverse Transcriptase Polymerase Chain Reaction , Salts/chemistry , Salts/metabolism , Salts/pharmacology , Structure-Activity Relationship
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