Induction of Mating in
 Candida albicans
 by Construction of
 MTL
 a and
 MTL
 α Strains

Magee, B. B.; Magee, Patrick

doi:10.1126/science.289.5477.310

Cited by 423 publications

(346 citation statements)

References 21 publications

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“…The discovery of the mating type locus of C. albicans (5) and subsequent description of fusion and mating (6,8,9,10,11) have provided a possible mechanism for recombination in natural C. albicans populations. Our initial data showing that a decrease in susceptibility and resistance to 5FC were exclusive characteristics of clade I, and the data presented here showing that a mutant allele of the FUR1 gene was dispersed throughout one clade but absent in non-clade I strains, suggest that if mating does occur, it happens only between members of the same clade.…”

Section: Discussionmentioning

confidence: 99%

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Dodgson¹,

Dodgson

Pujol³

et al. 2004

Antimicrob Agents Chemother

121

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Population studies have indicated that natural resistance to flucytosine (5FC) in Candida albicans is limited to one of the five major clades, clade I. In addition, while 73% of clade I isolates are less susceptible to 5FC (MIC > 0.5 g/ml), only 2% of non-clade I isolates are less susceptible. In order to determine the genetic basis for this clade-specific resistance, we sequenced two genes involved in the metabolism of 5FC that had previously been linked to resistance (cytosine deaminase and uracil phosphoribosyltransferase), in 48 isolates representative of all clades. Our results demonstrate that a single nucleotide change from cytosine to thymine at position 301 in the uracil phosphoribosyltransferase gene (FUR1) of C. albicans is responsible for 5FC resistance. The mutant allele was found only in group I isolates. The 5FC MICs for strains without copies of the mutant allele were almost exclusively <0.25 g/ml, those for strains with one copy of the mutant allele were >0.5 g/ml, and those for strains with two copies of the mutant allele were >16 g/ml. Thus, the two alleles were codominant. The presence of this allele is responsible for clade I-specific resistance to 5FC within the C. albicans population and thus by inference is likely to be the major underlying 5FC resistance mechanism in C. albicans. This represents the first description of the genetic mutation responsible for 5FC resistance.Analyses of the population structure of Candida albicans have revealed five major clades (I, II, III, SA, and E), each exhibiting a degree of geographical specificity (1,19,20,24). Recently, it was demonstrated that natural isolates that had been identified as resistant to flucytosine (5FC) were all members of clade I (18). Furthermore, it was demonstrated that 72% of clade I isolates exhibited reduced susceptibility to 5FC (5FC MIC Ն 0.5 g/ml) compared to 2% of non-clade I isolates (18). The fact that clades maintain their integrity side by side in the same geographical locale, combined with the observation that the majority of clade I isolates are less susceptible to 5FC, indicates that while recombination may occur within a clade, it may be a rare event between different clades (18,24), an interpretation consistent with earlier studies indicating that the population structure of C. albicans is primarily clonal (4,17).Although it has been demonstrated that natural resistance to 5FC is confined to isolates in clade I, the genetic basis of 5FC resistance has not been identified. 5FC enters a cell through the action of cytosine permease (15). Inside the cell, 5FC is converted to 5-fluorouracil (5FU) by cytosine deaminase, encoded by the gene FCY1 (7, 16). 5FU is then converted to 5-fluorouridine monophosphate by uracil phosphoribosyltransferase (UPRTase), encoded by the gene FUR1 (7, 16). 5-Fluorouridine monophosphate is then converted to 5-fluorouridine triphosphate, which, when incorporated into RNA in place of UTP, disrupts protein synthesis (7, 16). In addition, 5FU, when converted to 5-fluorodeoxyuridine monophosphat...

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Section: Discussionmentioning

confidence: 99%

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Dodgson¹,

Dodgson

Pujol³

et al. 2004

Antimicrob Agents Chemother

121

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“…Since the identification of a mating type-like ( MTL ) locus (Hull and Johnson, 1999) led to the discovery of mating in Candida albicans (Hull et al ., 2000;Magee and Magee, 2000), significant progress has been made in understanding the regulation and cell biology of the mating process in this organism. One of the most interesting facets of mating in C. albicans is the role of a phenomenon known as white-opaque switching.…”

Section: Introductionmentioning

confidence: 99%

“…Typically, only one of the parental nuclei would be inherited by the daughter cell, although sometimes both parental nuclei would enter the daughter cell, only to be segregated from one another in future cell divisions. On the surface, these observations appeared to be at odds with results from other laboratories, where the products of matingwhether from laboratory-derived strains or from clinical isolates -were tetraploid cells with a single nucleus (Hull et al ., 2000;Magee and Magee, 2000;Legrand et al ., 2004). In these latter studies, mating was scored by selecting for prototrophic mating products that had acquired genetic markers from both parents.…”

Section: Introductionmentioning

confidence: 99%

Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene

Bennett

Miller

Chua

et al. 2005

Molecular Microbiology

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SummaryIt is now well established that mating can occur between diploid a and a a a a cells of Candida albicans . There is, however, controversy over when, and with what efficiency, nuclear fusion follows cell fusion to create stable tetraploid a/ a a a a cells. In this study, we have analysed the mating process between C. albicans strains using both cytological and genetic approaches. Using strains derived from SC5314, we used a number of techniques, including time-lapse microscopy, to demonstrate that efficient nuclear fusion occurs in the zygote before formation of the first daughter cell. Consistent with these observations, zygotes micromanipulated from mating mixes gave rise to mononuclear tetraploid cells, even when no selection for successful mating was applied to them. Mating between different clinical isolates of C. albicans revealed that while all isolates could undergo nuclear fusion, the efficiency of nuclear fusion varied in different crosses. We also show that nuclear fusion in C. albicans requires the Kar3 microtubule motor protein. Deletion of the CaKAR3 gene from both mating partners had little or no effect on zygote formation but reduced the formation of stable tetraploids more than 600-fold, as determined by quantitative mating assays. These findings demonstrate that nuclear fusion is an active process that can occur in C. albicans at high frequency to produce stable, mononucleate mating products.

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“…But C. albicans has one additional and unique response to mating pheromones that so far has not been identified in other yeast . To mate, MTL-heterozygous strains of C. albicans must undergo homozygosis to a/a or ␣/␣ (Hull et al, 2000;Magee and Magee, 2000), then switch from the mating-incompetent white phenotype to the mating-competent opaque phenotype Lockhart et al, 2003a). Although pheromones induce mating responses in opaque a/a and ␣/␣ cells, including G1 arrest, polarization, and shmooing, as in S. cerevisiae, they do not induce these responses in white cells (Bennett et al, 2003; Lockhart et al, 2003a,b;Zhao et al, 2005a;Daniels et al, 2006).…”

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confidence: 99%

The Same Receptor, G Protein, and Mitogen-activated Protein Kinase Pathway Activate Different Downstream Regulators in the Alternative White and Opaque Pheromone Responses ofCandida albicans

Song

Sahni

Daniels

et al. 2008

MBoC

251

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Candida albicans must undergo a switch from white to opaque to mate. Opaque cells then release mating type-specific pheromones that induce mating responses in opaque cells. Uniquely in C. albicans, the same pheromones induce mating-incompetent white cells to become cohesive, form an adhesive basal layer of cells on a surface, and then generate a thicker biofilm that, in vitro, facilitates mating between minority opaque cells. Through mutant analysis, it is demonstrated that the pathways regulating the white and opaque cell responses to the same pheromone share the same upstream components, including receptors, heterotrimeric G protein, and mitogen-activated protein kinase cascade, but they use different downstream transcription factors that regulate the expression of genes specific to the alternative responses. This configuration, although common in higher, multicellular systems, is not common in fungi, and it has not been reported in Saccharomyces cerevisiae. The implications in the evolution of multicellularity in higher eukaryotes are discussed. INTRODUCTIONBoth single cell organisms and the individual cells of multicellular organisms must respond to a variety of environmental signals (Dorsky et al., 2000;Balázsi and Oltvai, 2005). In addition, in higher eukaryotes different cell types frequently respond to the same signal in unique ways (Rincón and Pedraza-Alva, 2003;Bacci et al., 2005;Dailey et al., 2005). In most cases, different signals interact with unique surface receptors that activate different signal transduction pathways, as has been demonstrated in Saccharomyces cerevisiae (Leberer et al., 1997;Gustin et al., 1998;Madhani and Fink, 1998;Elion, 2000). The mitogen-activated protein (MAP) kinase pathways have evolved as highly efficient, multipurpose signal transduction systems. S. cerevisiae uses multiple MAP kinase pathways, each one for a distinct signaling system, including the mating process, the filamentation process, cell wall integrity, ascospore formation, and osmoregulation (Levin and Errede, 1995;Gustin et al., 1998;Saito and Tatebayashi, 2004;Chen and Thorner, 2007). Several of these pathways share a limited number of components, but all are presumed to use different receptors to elicit very different responses. In the mating process of S. cerevisiae, a cells release a-factor that interacts with the a-receptor on ␣ cells, and ␣ cells release ␣-factor that interacts with the ␣-receptor on a cells. These alternative signals are then transduced through the same heterotrimeric G protein to activate the same MAP kinase pathway, which in turn activates the same downstream regulators that elicit similar mating responses, including G1 arrest, polarization, and shmooing (Sprague et al., 1983;Bender and Sprague, 1986;Leberer et al., 1997). Other fungi, including Magnaporthe grisea (Dixon et al., 1999;Zhao et al., 2005b) Neurospora crassa (Li et al., 2005), and Cryptococcus neoformans (Davidson et al., 2003;Kraus et al., 2003;Bahn et al., 2005) also use MAP kinase pathways for a variety of responses...

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Induction of Mating in Candida albicans by Construction of MTL a and MTL α Strains

Cited by 423 publications

References 21 publications

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene

The Same Receptor, G Protein, and Mitogen-activated Protein Kinase Pathway Activate Different Downstream Regulators in the Alternative White and Opaque Pheromone Responses ofCandida albicans

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