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Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation.
Daniel J Tomso1, Alberto Inga, Daniel Menendez
1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
Summary
Genetic variations in p53 response elements (REs) can alter cellular stress responses. This study identifies single nucleotide polymorphisms (SNPs) in p53 REs that impact gene expression, revealing new insights into the p53 pathway.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The p53 protein is a crucial tumor suppressor regulating cellular responses to DNA damage and stress.
- Genetic variations in p53 target gene promoter regions, specifically response elements (REs), can influence these stress responses.
- Understanding how these variations affect gene expression is vital for comprehending cancer development and treatment.
Purpose of the Study:
- To identify single nucleotide polymorphisms (SNPs) within p53 response elements (REs) that may alter p53-mediated gene expression.
- To functionally validate the impact of identified SNPs on p53 transactivation activity.
Main Methods:
- A bioinformatics approach was used to screen approximately 2 million human SNPs for potential disruption of functional p53 REs.
- Candidate SNPs were then tested using functional assays in yeast and mammalian cells to assess their effect on p53 transactivation.
- The activity of REs and the impact of SNPs on transactivation were evaluated.
Main Results:
- Over 200 SNPs were identified as potentially disrupting functional p53 REs.
- Eight candidate SNPs were functionally evaluated, all within functional REs.
- Each of the eight evaluated SNP pairs demonstrated differential transactivation capacities.
- Six of the eight associated genes are induced by genotoxic stress or activated by p53.
Conclusions:
- The developed strategy efficiently identifies SNPs that can differentially modulate gene expression within the p53 regulatory pathway.
- These identified SNPs represent potential genetic modifiers of cellular responses to stress and may have implications for cancer susceptibility and therapy.