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Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target

To understand disease mechanisms, a large-scale analysis of human–yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human–yeast genetic interactions were identified by en masse transformation of the human disease genes into a...

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Autores principales: Jo, Myungjin, Chung, Ah Young, Yachie, Nozomu, Seo, Minchul, Jeon, Hyejin, Nam, Youngpyo, Seo, Yeojin, Kim, Eunmi, Zhong, Quan, Vidal, Marc, Park, Hae Chul, Roth, Frederick P., Suk, Kyoungho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580709/
https://www.ncbi.nlm.nih.gov/pubmed/28596290
http://dx.doi.org/10.1101/gr.211649.116
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author Jo, Myungjin
Chung, Ah Young
Yachie, Nozomu
Seo, Minchul
Jeon, Hyejin
Nam, Youngpyo
Seo, Yeojin
Kim, Eunmi
Zhong, Quan
Vidal, Marc
Park, Hae Chul
Roth, Frederick P.
Suk, Kyoungho
author_facet Jo, Myungjin
Chung, Ah Young
Yachie, Nozomu
Seo, Minchul
Jeon, Hyejin
Nam, Youngpyo
Seo, Yeojin
Kim, Eunmi
Zhong, Quan
Vidal, Marc
Park, Hae Chul
Roth, Frederick P.
Suk, Kyoungho
author_sort Jo, Myungjin
collection PubMed
description To understand disease mechanisms, a large-scale analysis of human–yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human–yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.
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spelling pubmed-55807092017-09-14 Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target Jo, Myungjin Chung, Ah Young Yachie, Nozomu Seo, Minchul Jeon, Hyejin Nam, Youngpyo Seo, Yeojin Kim, Eunmi Zhong, Quan Vidal, Marc Park, Hae Chul Roth, Frederick P. Suk, Kyoungho Genome Res Research To understand disease mechanisms, a large-scale analysis of human–yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human–yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases. Cold Spring Harbor Laboratory Press 2017-09 /pmc/articles/PMC5580709/ /pubmed/28596290 http://dx.doi.org/10.1101/gr.211649.116 Text en © 2017 Jo et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Jo, Myungjin
Chung, Ah Young
Yachie, Nozomu
Seo, Minchul
Jeon, Hyejin
Nam, Youngpyo
Seo, Yeojin
Kim, Eunmi
Zhong, Quan
Vidal, Marc
Park, Hae Chul
Roth, Frederick P.
Suk, Kyoungho
Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
title Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
title_full Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
title_fullStr Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
title_full_unstemmed Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
title_short Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
title_sort yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of map2k5 kinase as a potential drug target
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580709/
https://www.ncbi.nlm.nih.gov/pubmed/28596290
http://dx.doi.org/10.1101/gr.211649.116
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