Chromosome translocation induced by the insertion of the <i>URA</i> blaster into the major repeat sequence (MRS) in <i>Candida albicans</i>

Iwaguchi, Shin-Ichi; Suzuki, Mina; Sakai, Naomi; Nakagawa, Yoshiyuki; Magee, Patrick; Suzuki, Takahito

doi:10.1002/yea.1116

Cited by 9 publications

(5 citation statements)

References 32 publications

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“…Our work suggests that several mechanisms contribute to LOH, which is consistent with the recognized elasticity of the C. albicans genome (Iwaguchi et al 2001;X. Chen et al 2004;Iwaguchi et al 2004). Although the number of isolates investigated here was limited, LOH at chromosome 5 was obtained by mitotic recombination in the investigated clinical isolates, whereas it was obtained by chromosome 5 loss and duplications in laboratory conditions.…”

Section: Discussionsupporting

confidence: 85%

A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

Coste¹,

Turner²,

Ischer³

et al. 2006

Genetics

350

359

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TAC1, a Candida albicans transcription factor situated near the mating-type locus on chromosome 5, is necessary for the upregulation of the ABC-transporter genes CDR1 and CDR2, which mediate azole resistance. We showed previously the existence of both wild-type and hyperactive TAC1 alleles. Wild-type alleles mediate upregulation of CDR1 and CDR2 upon exposure to inducers such as fluphenazine, while hyperactive alleles result in constitutive high expression of CDR1 and CDR2. Here we recovered TAC1 alleles from two pairs of matched azole-susceptible (DSY294; FH1: heterozygous at mating-type locus) and azole-resistant isolates (DSY296; FH3: homozygous at mating-type locus). Two different TAC1 wild-type alleles were recovered from DSY294 (TAC1-3 and TAC1-4) while a single hyperactive allele (TAC1-5) was isolated from DSY296. A single amino acid (aa) difference between TAC1-4 and TAC1-5 (Asn977 to Asp or N977D) was observed in a region corresponding to the predicted activation domain of Tac1p. Two TAC1 alleles were recovered from FH1 (TAC1-6 and TAC1-7) and a single hyperactive allele (TAC1-7) was recovered from FH3. The N977D change was seen in TAC1-7 in addition to several other aa differences. The importance of N977D in conferring hyperactivity to TAC1 was confirmed by site-directed mutagenesis. Both hyperactive alleles TAC1-5 and TAC1-7 were codominant with wild-type alleles and conferred hyperactive phenotypes only when homozygous. The mechanisms by which hyperactive alleles become homozygous was addressed by comparative genome hybridization and single nucleotide polymorphism arrays and indicated that loss of TAC1 heterozygosity can occur by recombination between portions of chromosome 5 or by chromosome 5 duplication. C ANDIDA albicans is an opportunistic pathogen that causes oral and systemic infections in immunocompromised patients as well as vaginal infections in immunocompetent women. To prevent and treat Candida infections, immunocompromised patients are often treated for a long time with antifungal agents among which is the class of azoles. As azoles are fungistatic, rather than fungicidal, C. albicans cells repetitively exposed to these antifungals can adapt to the drug pressure and eventually become resistant to azoles. The most important mechanism of resistance to azoles is the overexpression of multidrug transporters, encoded by either the major facilitator efflux pump CaMDR1 (multidrug resistance 1) or the ABC transporters CDR1 (candida drug resistance) and CDR2. Upregulation of CaMDR1 confers resistance to fluconazole, while upregulation of CDR1 and CDR2 confers resistance to multiple azoles (itraconazole, fluconazole, voriconazole). Understanding the transcriptional control of these genes, by both cis-and trans-acting effectors, is therefore important for determining how azole resistance and transport mechanisms are regulated in C. albicans.CaMDR1 expression is controlled by at least two regulatory promoter cis-acting regions as reported recently by Harry et al. (2005). Several elements of...

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Section: Discussionsupporting

confidence: 85%

A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

Coste¹,

Turner²,

Ischer³

et al. 2006

Genetics

350

359

View full text Add to dashboard Cite

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“…The control of the translocation process is not understood, and most translocations seem to occur either during growth in the host or when induced by chromosome damage in vitro (Iwaguchi et al 2004). And since heterologous translocations do not alter the genetic composition of the affected cell ( just its genomic arrangement), they are difficult to detect except by analysis of the karyotypes of all potential translocatants.…”

Section: Discussionmentioning

confidence: 99%

“…The MRS also has a well-documented history of association with genome rearrangements and translocations in numerous clinical isolates (Chu et al 1993;Lockhart et al 1995;Chibana et al 2000;Iwaguchi et al 2000Iwaguchi et al , 2001. Chromosome rearrangements have also been induced at a high frequency in the laboratory by introduction of foreign DNA into the MRS (Iwaguchi et al 2004). However, spontaneous translocation is an infrequent event in C. albicans in the laboratory and has rarely been observed.…”

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confidence: 99%

Effect of the Major Repeat Sequence on Mitotic Recombination in Candida albicans

Lephart

Magee

2006

Genetics

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The major repeat sequence (MRS) is known to play a role in karyotypic variation in Candida albicans. The MRS affects karyotypic variation by expanding and contracting internal repeats, by altering the frequency of chromosome loss, and by serving as a hotspot for chromosome translocation. We proposed that the effects of the MRS on translocation could be better understood by examination of the effect of the MRS on a similar event, mitotic recombination between two chromosome homologs. We examined the frequency of mitotic recombination across an MRS of average size ($50 kb) as well as the rate of recombination in a 325-kb stretch of DNA adjacent to the MRS. Our results indicate that mitotic recombination frequencies across the MRS were not enhanced compared to the frequencies measured across the 325-kb region adjacent to the MRS. Mitotic recombination events were found to occur throughout the 325-kb region analyzed as well as within the MRS itself. This analysis of mitotic recombination frequencies across a large portion of chromosome 5 is the first large-scale analysis of mitotic recombination done in C. albicans and indicates that mitotic recombination frequencies are similar to the rates found in Saccharomyces cerevisiae.

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“…The control of the translocation process is not understood, and most translocations seem to occur either during growth in the host or when induced by chromosome damage in vitro (15). If the MRS is the location for translocations between heterologous chromosomes, as the data would suggest, it may also play a role in translocations between homologous chromosomes via mitotic recombination.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Major Repeat Sequence on Chromosome Loss in Candida albicans

2005

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The major repeat sequence (MRS) is found at least once on all but one chromosome in Candida albicans, but as yet it has no known relation to the phenotype. The MRS affects karyotypic variation by serving as a hot spot for chromosome translocation and by expanding and contracting internal repeats, thereby changing chromosome length. Thus, MRSs on different chromosomes and those on chromosome homologues can differ in size. We proposed that the MRS's unique repeat structure and, more specifically, the size of the MRS could also affect karyotypic variation by altering the frequency of mitotic nondisjunction. Subsequent analysis shows that both natural and artificially induced differences in the size of the chromosome 5 MRS can affect chromosome segregation. Strains with chromosome 5 homologues that differ in the size of the naturally occurring MRSs show a preferential loss of the homologue with the larger MRS on sorbose, indicating that a larger MRS leads to a higher risk of mitotic nondisjunction for that homologue. While deletion of an MRS has no deleterious effect on the deletion chromosome under normal growth conditions and leads to no obvious phenotype, strains that have the MRS deleted from one chromosome 5 homologue preferentially lose the homologue with the MRS remaining. This effect on chromosome segregation is the first demonstration of a phenotype associated with the MRS.

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Chromosome translocation induced by the insertion of the URA blaster into the major repeat sequence (MRS) in Candida albicans

Cited by 9 publications

References 32 publications

A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

Effect of the Major Repeat Sequence on Mitotic Recombination in Candida albicans

Effect of the Major Repeat Sequence on Chromosome Loss in Candida albicans

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