Related Experiment Video
Updated: Jul 4, 2026
09:10
A Fast and Quantitative Method for Post-translational Modification and Variant Enabled Mapping of Peptides to Genomes
Published on: May 22, 2018
Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics
Liewei Wang1, Shaji Kumar, Brooke L Fridley
1Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. wang.liewei@mayo.edu
Summary
Genetic variations in the PSMB5 gene influence proteasome transcription but not activity. These findings highlight the importance of studying regulatory region polymorphisms for understanding proteasome function and drug response.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Biology
Background:
- The proteasome is a critical cellular organelle responsible for protein degradation, regulating diverse cellular processes.
- Proteasome inhibitors are key antineoplastic drugs, and genetic variations in proteasome subunits may affect drug efficacy.
- Understanding genetic variations in proteasome genes is crucial for personalized cancer therapy.
Purpose of the Study:
- To investigate genetic variations in proteasome beta subunits, focusing on PSMB5, the target of bortezomib.
- To determine the functional impact of identified polymorphisms on gene transcription and proteasome activity.
- To explore ethnic-specific genetic variations and their potential influence on proteasome function.
Main Methods:
- Resequencing of genes encoding three active proteasome beta subunits in 240 DNA samples from diverse ethnic groups.
- Functional analysis of identified polymorphisms in the coding and 3'-flanking regions (3'-FR) of the PSMB5 gene using reporter gene assays.
- Genotype-phenotype correlation studies linking PSMB5 single nucleotide polymorphisms (SNPs) to mRNA expression levels in lymphoblastoid cell lines.
Main Results:
- Identification of novel, ethnic-specific polymorphisms in proteasome subunit genes, including PSMB5, not present in public databases.
- The PSMB5 3'-FR 1042 G allele was found to significantly increase gene transcription, confirmed by genotype-phenotype correlations.
- Novel PSMB5 polymorphisms in the 3'-FR, including a SNP and an insertion, were identified in patient samples and shown to potentially decrease transcription.
Conclusions:
- Nonsynonymous coding SNPs in the PSMB5 gene do not significantly alter proteasome activity.
- Genetic variations, particularly in regulatory regions like the 3'-FR of PSMB5, can modulate gene transcription.
- Future research should prioritize investigating regulatory region polymorphisms to fully understand their impact on proteasome function and drug response.
Related Concept Videos
01:29Pharmacogenomics: Identification of New Drug Targets
Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:29Pharmacogenetics and Pharmacogenomics: Overview
Pharmacogenetics and pharmacogenomics examine how genetic factors influence an individual's response to drugs. While pharmacogenetics focuses on the impact of specific genetic variants on drug effects, pharmacogenomics takes a broader approach, studying how genetic variation across populations contributes to differences in drug responses. These fields aim to explain why individuals may experience varying levels of efficacy or adverse reactions to the same medication.Variability in drug...
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:33Proteomics
A proteome is the entire set of proteins that a cell type produces. We can study proteomes using the knowledge of genomes because genes code for mRNAs, and the mRNAs encode proteins. Although mRNA analysis is a step in the right direction, not all mRNAs are translated into proteins.
Proteomics is the study of proteomes' function. It involves the large-scale systematic study of the proteome to denote the protein complement expressed by a genome. Scientist Mark Wilkins coined the term proteomics...
Proteomics is the study of proteomes' function. It involves the large-scale systematic study of the proteome to denote the protein complement expressed by a genome. Scientist Mark Wilkins coined the term proteomics...
01:27Principles of Pharmacogenetics: Types of Genetic Variants
The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...