Computational Analysis of MDR1 Variants Predicts Effect on Cancer Cells via their Effect on mRNA Folding

Sep 21, 2026

Uploaded by Theodora

The study investigates how genetic variants within the MDR1 gene influence P-glycoprotein, an ATP-driven drug efflux transporter associated with multi-drug resistance in cancer. Three single nucleotide polymorphisms (T1236C, T2677G, and T3435C) are evaluated using a computational, data-driven framework focused on key stages of gene expression. Results indicate that all three variants significantly alter nearby mRNA folding and are predicted to increase local translation elongation rates. Notably, T3435C is predicted to affect co-translational protein folding at the second ATP binding domain, potentially impacting conformation, function, prognosis, and resistance.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages32

Reading Time1 h 21 min

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Abstract

Introduction

Author Summary

PLOS COMPUTATIONAL BIOLOGY OPEN ACCESS Citation: Gutman T, Tuller T (2024) Computational Analysis of MDR1 Variants Predicts Effect on Cancer Cells via their Effect on mRNA Folding. PLoS Comput Biol 20(12): e1012685 . [https://doi](https://doi). org/10 .1371/journal.pcbi.1012685 Editor: Mohammad Sadegh Taghizadeh, Shiraz University, ISLAMIC REPUBLIC OF IRAN Received: September 4, 2024 Accepted: November 29, 2024 Published: December 26, 2024 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: [https://doi.org/10.1371/journal.pcbi.1012685](https://doi.org/10.1371/journal.pcbi.1012685) [Copyright:](Copyright:) © [2024 Gutman](2024 Gutman), [Tuller](Tuller). This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Code can be downloaded from [https://www.cs.tau.ac.il/](https://www.cs.tau.ac.il/)~tamirtul/Co-Trans-FE. Non-confidential data is available on Zenodo (10.5281/zenodo.14050188) and protected data is available through the RESEARCH ARTICLE Computational Analysis of MDR1 Variants Predicts Effect on Cancer Cells via their Effect on mRNA Folding Tal Gutman1, Tamir Tuller1,2 * 1 Department of Biomedical Engineering, the Engineering Faculty, Tel Aviv University, Tel-Aviv, Israel, 2 The Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel * [tamirtul@tauex.tau.ac.il](tamirtul@tauex.tau.ac.il) Abstract The P-glycoprotein efflux pump, encoded by the MDR1 gene, is an ATP-driven transporter capable of expelling a diverse array of compounds from cells. Overexpression of this protein is implicated in the multi-drug resistant phenotype observed in various cancers. Numerous studies have attempted to decipher the impact of genetic variants within MDR1 on P-glycoprotein expression, functional activity, and clinical outcomes in cancer patients. Among these, three specific single nucleotide polymorphisms—T1236C, T2677G, and T3435Chave been the focus of extensive research efforts, primarily through in vitro cell line models and clinical cohort analyses. However, the findings from these studies have been remarkably contradictory. In this study, we employ a computational, data-driven approach to systematically evaluate the effects of these three variants on principal stages of the gene expression process. Leveraging current knowledge of gene regulatory mechanisms, we elucidate potential mechanisms by which these variants could modulate P-glycoprotein levels and function. Our findings suggest that all three variants significantly change the mRNA folding in their vicinity. This change in mRNA structure is predicted to increase local translation elongation rates, but not to change the protein expression. Nonetheless, the increased translation rate near T3435C is predicted to affect the protein’s co-translational folding trajectory in the region of the second ATP binding domain. This potentially impacts P-glycoprotein conformation and function. Our study demonstrates the value of computational approaches in elucidating the functional consequences of genetic variants. This framework provides new insights into the molecular mechanisms of MDR1 variants and their potential impact on cancer prognosis and treatment resistance. Furthermore, we introduce an approach which can be systematically applied to identify mutations potentially affecting mRNA folding in pathology. We demonstrate the utility of this approach on both ClinVar and TCGA and identify hundreds of disease related variants that modify mRNA folding at essential positions. PLOS Computational Biology | [https://d

FAQs

What MDR1 gene variants are analyzed in the study?

The study focuses on three MDR1 single nucleotide polymorphisms: T1236C, T2677G, and T3435C.

How does the study evaluate the effects of these variants?

It uses a computational, data-driven approach to systematically assess impacts on principal stages of the gene expression process, with emphasis on mRNA folding and downstream translation effects.

What main effects on mRNA and translation are predicted?

All three variants are predicted to significantly change local mRNA folding and to increase local translation elongation rates.

Sep 21, 2026

Uploaded by Theodora