TY - GEN
T1 - Revisiting the Effects of MDR1 Variants Using Computational Approaches
AU - Gutman, Tal
AU - Tuller, Tamir
N1 - Publisher Copyright:
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024.
PY - 2024
Y1 - 2024
N2 - P-glycoprotein, encoded by the MDR1 gene, is an ATP-dependent pump that exports various substances out of cells. Its overexpression is related to multi drug resistance in many cancers. Numerous studies explored the effects of MDR1 variants on p-glycoprotein expression and function, and on patient survivability. T1236C, T2677G and T3435C are prevalent MDR1 variants that are the most widely studied, typically in-vitro and in-vivo, with remarkably inconsistent results. In this paper we perform computational, data-driven analyses to assess the effects of these variants using a different approach. We use knowledge of gene expression regulation to elucidate the variants’ mechanism of action. Results indicate that T1236C is correlated with worse patient prognosis. Additionally, examination of MDR1 folding strength suggests that T3435C potentially modifies co-translational folding. Furthermore, all three variants reside in potential translation bottlenecks and likely cause increased translation rates. These results support several hypotheses suggested by previous studies. To the best of our knowledge, this study is the first to apply a computational approach to examine the effects of MDR1 variants.
AB - P-glycoprotein, encoded by the MDR1 gene, is an ATP-dependent pump that exports various substances out of cells. Its overexpression is related to multi drug resistance in many cancers. Numerous studies explored the effects of MDR1 variants on p-glycoprotein expression and function, and on patient survivability. T1236C, T2677G and T3435C are prevalent MDR1 variants that are the most widely studied, typically in-vitro and in-vivo, with remarkably inconsistent results. In this paper we perform computational, data-driven analyses to assess the effects of these variants using a different approach. We use knowledge of gene expression regulation to elucidate the variants’ mechanism of action. Results indicate that T1236C is correlated with worse patient prognosis. Additionally, examination of MDR1 folding strength suggests that T3435C potentially modifies co-translational folding. Furthermore, all three variants reside in potential translation bottlenecks and likely cause increased translation rates. These results support several hypotheses suggested by previous studies. To the best of our knowledge, this study is the first to apply a computational approach to examine the effects of MDR1 variants.
KW - MDR1
KW - cancer evolution
KW - gene expression
KW - mRNA folding selection
KW - synonymous variants
UR - http://www.scopus.com/inward/record.url?scp=85192267264&partnerID=8YFLogxK
U2 - 10.1007/978-3-031-58072-7_12
DO - 10.1007/978-3-031-58072-7_12
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AN - SCOPUS:85192267264
SN - 9783031580710
T3 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
SP - 226
EP - 247
BT - Comparative Genomics - 21st International Conference, RECOMB-CG 2024, Proceedings
A2 - Scornavacca, Celine
A2 - Hernández-Rosales, Maribel
PB - Springer Science and Business Media Deutschland GmbH
T2 - 21st RECOMB International Workshop on Comparative Genomics, RECOMB-CG 2024
Y2 - 27 April 2024 through 28 April 2024
ER -