Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection.
Candida albicans is the most common human fungal pathogen, causing infections that can be lethal in immunocompromised patients. Although Saccharomyces cerevisiae has been used as a model for C. albicans, it lacks C. albicans' diverse morphogenic forms and is primarily non-pathogenic. Comprehens...
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2010-10-01
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doaj-9ab6f1abee464007aafcfeb107fa56c12020-11-25T01:58:26ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-10-01610e100114010.1371/journal.ppat.1001140Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection.Julia OhEula FungUlrich SchlechtRonald W DavisGuri GiaeverRobert P St OngeAdam DeutschbauerCorey NislowCandida albicans is the most common human fungal pathogen, causing infections that can be lethal in immunocompromised patients. Although Saccharomyces cerevisiae has been used as a model for C. albicans, it lacks C. albicans' diverse morphogenic forms and is primarily non-pathogenic. Comprehensive genetic analyses that have been instrumental for determining gene function in S. cerevisiae are hampered in C. albicans, due in part to limited resources to systematically assay phenotypes of loss-of-function alleles. Here, we constructed and screened a library of 3633 tagged heterozygous transposon disruption mutants, using them in a competitive growth assay to examine nutrient- and drug-dependent haploinsufficiency. We identified 269 genes that were haploinsufficient in four growth conditions, the majority of which were condition-specific. These screens identified two new genes necessary for filamentous growth as well as ten genes that function in essential processes. We also screened 57 chemically diverse compounds that more potently inhibited growth of C. albicans versus S. cerevisiae. For four of these compounds, we examined the genetic basis of this differential inhibition. Notably, Sec7p was identified as the target of brefeldin A in C. albicans screens, while S. cerevisiae screens with this compound failed to identify this target. We also uncovered a new C. albicans-specific target, Tfp1p, for the synthetic compound 0136-0228. These results highlight the value of haploinsufficiency screens directly in this pathogen for gene annotation and drug target identification.http://europepmc.org/articles/PMC2951378?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julia Oh Eula Fung Ulrich Schlecht Ronald W Davis Guri Giaever Robert P St Onge Adam Deutschbauer Corey Nislow |
spellingShingle |
Julia Oh Eula Fung Ulrich Schlecht Ronald W Davis Guri Giaever Robert P St Onge Adam Deutschbauer Corey Nislow Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. PLoS Pathogens |
author_facet |
Julia Oh Eula Fung Ulrich Schlecht Ronald W Davis Guri Giaever Robert P St Onge Adam Deutschbauer Corey Nislow |
author_sort |
Julia Oh |
title |
Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. |
title_short |
Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. |
title_full |
Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. |
title_fullStr |
Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. |
title_full_unstemmed |
Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. |
title_sort |
gene annotation and drug target discovery in candida albicans with a tagged transposon mutant collection. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2010-10-01 |
description |
Candida albicans is the most common human fungal pathogen, causing infections that can be lethal in immunocompromised patients. Although Saccharomyces cerevisiae has been used as a model for C. albicans, it lacks C. albicans' diverse morphogenic forms and is primarily non-pathogenic. Comprehensive genetic analyses that have been instrumental for determining gene function in S. cerevisiae are hampered in C. albicans, due in part to limited resources to systematically assay phenotypes of loss-of-function alleles. Here, we constructed and screened a library of 3633 tagged heterozygous transposon disruption mutants, using them in a competitive growth assay to examine nutrient- and drug-dependent haploinsufficiency. We identified 269 genes that were haploinsufficient in four growth conditions, the majority of which were condition-specific. These screens identified two new genes necessary for filamentous growth as well as ten genes that function in essential processes. We also screened 57 chemically diverse compounds that more potently inhibited growth of C. albicans versus S. cerevisiae. For four of these compounds, we examined the genetic basis of this differential inhibition. Notably, Sec7p was identified as the target of brefeldin A in C. albicans screens, while S. cerevisiae screens with this compound failed to identify this target. We also uncovered a new C. albicans-specific target, Tfp1p, for the synthetic compound 0136-0228. These results highlight the value of haploinsufficiency screens directly in this pathogen for gene annotation and drug target identification. |
url |
http://europepmc.org/articles/PMC2951378?pdf=render |
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