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Paralog-based synthetic lethality: rationales and applications

Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed...

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Detalles Bibliográficos
Autores principales: Xin, Yucui, Zhang, Yingsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10282757/
https://www.ncbi.nlm.nih.gov/pubmed/37350942
http://dx.doi.org/10.3389/fonc.2023.1168143
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author Xin, Yucui
Zhang, Yingsheng
author_facet Xin, Yucui
Zhang, Yingsheng
author_sort Xin, Yucui
collection PubMed
description Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed. Paralogs, a set of homologous genes that have diverged from each other as a consequence of gene duplication, make the concept of SL feasible as the loss of one gene does not affect the cell’s survival. Furthermore, homozygous loss of paralogs in tumor cells is more frequent than singletons, making them ideal SL targets. Although high-throughput CRISPR-Cas9 screenings have uncovered numerous paralog-based SL pairs, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors that exclusively target a single but not both paralogs hinder further clinical development. Here, we review the potential mechanisms of paralog-based SL given their function and genetic combination, and discuss the challenge and application prospects of paralog-based SL in cancer therapeutic discovery.
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spelling pubmed-102827572023-06-22 Paralog-based synthetic lethality: rationales and applications Xin, Yucui Zhang, Yingsheng Front Oncol Oncology Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed. Paralogs, a set of homologous genes that have diverged from each other as a consequence of gene duplication, make the concept of SL feasible as the loss of one gene does not affect the cell’s survival. Furthermore, homozygous loss of paralogs in tumor cells is more frequent than singletons, making them ideal SL targets. Although high-throughput CRISPR-Cas9 screenings have uncovered numerous paralog-based SL pairs, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors that exclusively target a single but not both paralogs hinder further clinical development. Here, we review the potential mechanisms of paralog-based SL given their function and genetic combination, and discuss the challenge and application prospects of paralog-based SL in cancer therapeutic discovery. Frontiers Media S.A. 2023-06-07 /pmc/articles/PMC10282757/ /pubmed/37350942 http://dx.doi.org/10.3389/fonc.2023.1168143 Text en Copyright © 2023 Xin and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Xin, Yucui
Zhang, Yingsheng
Paralog-based synthetic lethality: rationales and applications
title Paralog-based synthetic lethality: rationales and applications
title_full Paralog-based synthetic lethality: rationales and applications
title_fullStr Paralog-based synthetic lethality: rationales and applications
title_full_unstemmed Paralog-based synthetic lethality: rationales and applications
title_short Paralog-based synthetic lethality: rationales and applications
title_sort paralog-based synthetic lethality: rationales and applications
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10282757/
https://www.ncbi.nlm.nih.gov/pubmed/37350942
http://dx.doi.org/10.3389/fonc.2023.1168143
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