Rad52 function prevents chromosome loss and truncation in <i>Candida albicans</i>

Andaluz, Encarnación; Bellido, Alberto; Gómez-Raja, Jonathan; Selmecki, Anna; Bouchonville, Kelly J.; Calderone, Richard; Berman, Judith; Larriba, Germán

doi:10.1111/j.1365-2958.2011.07532.x

Cited by 28 publications

(56 citation statements)

References 92 publications

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“…Chromosome homozygosis was long thought to be hampered in C. albicans by the presence of recessive lethal mutations dispersed throughout the genome. The existence of haploids (2), completely homozygous rad52-derived isolates (55), and partly homozygous diploid parasexual progenies (56) demonstrated that homozygosis of each one of the eight chromosomes can occur. Nevertheless, a bias in the homolog being retained was reported for certain chromosomes (2,55).…”

Section: Discussionmentioning

confidence: 99%

“…The existence of haploids (2), completely homozygous rad52-derived isolates (55), and partly homozygous diploid parasexual progenies (56) demonstrated that homozygosis of each one of the eight chromosomes can occur. Nevertheless, a bias in the homolog being retained was reported for certain chromosomes (2,55). This was the case for Ch4, one homolog of which could never be lost (2,55).…”

Section: Discussionmentioning

confidence: 99%

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A FACS-Optimized Screen Identifies Regulators of Genome Stability in Candida albicans

et al. 2015

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f Loss of heterozygosity (LOH) plays important roles in genome dynamics, notably, during tumorigenesis. In the fungal pathogen Candida albicans, LOH contributes to the acquisition of antifungal resistance. In order to investigate the mechanisms that regulate LOH in C. albicans, we have established a novel method combining an artificial heterozygous locus harboring the blue fluorescent protein and green fluorescent protein markers and flow cytometry to detect LOH events at the single-cell level. Using this fluorescence-based method, we have confirmed that elevated temperature, treatment with methyl methanesulfonate, and inactivation of the Mec1 DNA damage checkpoint kinase triggered an increase in the frequency of LOH. Taking advantage of this system, we have searched for C. albicans genes whose overexpression triggered an increase in LOH and identified four candidates, some of which are known regulators of genome dynamics with human homologues contributing to cancer progression. Hence, the approach presented here will allow the implementation of new screens to identify genes that are important for genome stability in C. albicans and more generally in eukaryotic cells.N ormally found as a harmless commensal organism, Candida albicans is also a major fungal pathogen of humans and is capable of causing serious and even life-threatening diseases when the immune system of the host is compromised (1). Although C. albicans is found mostly as a diploid organism, haploid and tetraploid forms have been observed in the laboratory and upon the passage of C. albicans in animal models of infection (2-4). The formation of tetraploids results from mating between diploids of opposite mating types that have undergone the so-called whiteopaque phenotypic switch (5). Meiosis is thought to have been lost in C. albicans, and the formation of haploids from diploids or diploids from tetraploids results from concerted chromosome loss (2, 6). The C. albicans genome is highly plastic, undergoing a number of important genome rearrangements, such as loss-ofheterozygosity (LOH) events, aneuploidies, and the formation of isochromosomes (7). In particular, LOH has been shown to occur during commensal carriage (8) and during systemic infection in a mouse model (9) and to contribute to the acquisition of antifungal resistance (10, 11). Stressful conditions such as high temperature, oxidative stress, or azole antifungal treatment trigger an increase in the frequency of LOH, as well as changes in the mechanisms leading to LOH; while azole treatment and temperature cause an increase in LOH due to chromosome loss and reduplication, oxidative stress results in an increase in gene conversion events (12). Yet, little is known about the molecular mechanisms that control LOH in C. albicans, despite the apparent importance of LOH in the biology of this species. Overall, it has been shown that knockout mutations in genes involved in base excision repair, nucleotide excision repair, and mismatch repair had little impact on the frequency of LOH in C. albican...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A FACS-Optimized Screen Identifies Regulators of Genome Stability in Candida albicans

et al. 2015

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“…There is a slight, but reproducible difference in MMS sensitivity between CAI4-L and CAI4 ( Figure 9A). When we compare their SNP/CGH profiles, a homozygous region is evident on Chr2L in CAI4-L, whereas heterozygosity is maintained in CAI4 ( Figure 2B) Andaluz et al 2011). In CAI4-L, this LOH occurred via an interhomolog recombination event at coordinate 1,656,168 and we Figure 6 Proposed mechanisms for the generation of the several P strains (FOA R segregants) derived from URA3 transformants T6 and T7 as deduced from the SNP-CGH results.…”

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confidence: 84%

“…In this regard, some CAI4 stocks carry additional regions of LOH, such as CAI4-L, which has Chr2L long-range LOH and no detectable aneuploidy (Andaluz et al 2011). We cannot distinguish whether this long-range LOH was spontaneous or a result of unknown stress.…”

Section: Loss Of Heterozygosity In Candida Albicansmentioning

confidence: 95%

“…For Chr3R, pink is a, and for Chr2L, blue is a. Unambiguous ascription of LOH regions to aa or bb alleles according to current GCD assembly 22 required analysis of individual SNPs and is indicated in the text (see also Andaluz et al 2011). unchanged ( Figure 1B). Similarly, supplementing uridine to the growth media resulted in slight growth improvements at 28°but not at 43°in CAI4-L and its Uri + derivatives (TSC570 and TSC571) (not shown).…”

Section: Mms and Temperature Sensitivity Is Independent Of Ura3 Exprementioning

confidence: 99%

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Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

et al. 2016

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By testing the susceptibility to DNA damaging agents of several Candida albicans mutant strains derived from the commonly used laboratory strain, CAI4, we uncovered sensitivity to methyl methanesulfonate (MMS) in CAI4 and its derivatives, but not in CAF2-1. This sensitivity is not a result of URA3 disruption because the phenotype was not restored after URA3 reintroduction. Rather, we found that homozygosis of a short region of chromosome 3R (Chr3R), which is naturally heterozygous in the MMS-resistant-related strains CAF4-2 and CAF2-1, confers MMS sensitivity and modulates growth polarization in response to MMS. Furthermore, induction of homozygosity in this region in CAF2-1 or CAF4-2 resulted in MMS sensitivity. We identified 11 genes by SNP/comparative genomic hybridization containing only the a alleles in all the MMS-sensitive strains. Four candidate genes, SNF5, POL1, orf19.5854.1, and MBP1, were analyzed by generating hemizygous configurations in CAF2-1 and CAF4-2 for each allele of all four genes. Only hemizygous MBP1a/mbp1b::SAT1-FLIP strains became MMS sensitive, indicating that MBP1a in the homo-or hemizygosis state was sufficient to account for the MMS-sensitive phenotype. In yeast, Mbp1 regulates G1/S genes involved in DNA repair. A second region of homozygosis on Chr2L increased MMS sensitivity in CAI4 (Chr3R homozygous) but not CAF4-2 (Chr3R heterozygous). This is the first example of sign epistasis in C. albicans.KEYWORDS Candida albicans; LOH; MMS susceptibility; MBP1; growth polarization T HE opportunistic fungal pathogen Candida albicans is often isolated as a highly heterozygous diploid; the genome of the reference strain SC5314 has 67,500 single nucleotide polymorphisms (SNPs) (Jones et al. 2004;Braun et al. 2005;Muzzey et al. 2013). SNPs found within regulatory regions can affect transcription levels between the alleles (Staib et al. 2002). Even synonymous SNPs residing in open reading frames (ORFS) can result in differences in the rate and efficiency of messenger RNA (mRNA) translation since poorly used codons delay protein synthesis. These delays may lead to misfolding of the nascent protein or formation of mRNA secondary structures (reviewed in Larriba and Calderone 2008). Recent genome-wide analysis of cis elements on gene expression showed that allele-specific effects are often due to mRNA levels and/or translation efficiency (Muzzey et al. 2014).While the majority of SNPs reside in intergenic regions, more than half of open reading frames contain one or more SNPs. The vast majority (78%) of these are nonsynonymous, implying that a significant fraction of ORFs encode proteins that differ in one or more amino acids (Jones et al. 2004) that may affect crucial properties. Nonconservative amino acid substitutions within an enzyme's catalytic domain could result in an inactive allele (Gómez-Raja et al. 2008). However, many SNPs will cause only minor or insignificant alterations in protein properties.Mitotic recombination or less frequently, chromosome truncation or loss, will reveal ...

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Ploidy changes and genome stability in yeast

Storchová

2014

Yeast

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Eukaryotic organisms maintain karyotypes with constant chromosome number, but polyploid cells that contain more than two sets of chromosomes can frequently be found. On the one hand, polyploidization is likely to provide some beneficial effects, as naturally occurring polyploid cells can be readily found. On the other hand, polyploidization profoundly affects cell physiology, which may be detrimental to cells. Additionally, polyploidy leads often to aneuploidy and diversification of genetic information; therefore, it has always been considered a prominent driving force in evolution. Recently tetraploid-derived aneuploidy was suggested as a possible mechanism for resistance to fungicides. Another prominent example of the effects of tetraploid-derived aneuploidy is cancer, in which up to one-third of tumours likely originate through tetraploid intermediates. Studying the cellular consequences of polyploidization in human cells is challenging. In contrast, polyploid and aneuploid cells can be easily generated and analysed in the budding yeast Saccharomyces cerevisiae as well as in other yeast species. This, together with the naturally occurring yeast polyploids and aneuploids, provides a valuable model to study the effects of abnormal chromosome numbers on cellular physiology. Thus, the yeast model may provide novel insights into the general mechanisms of genomic instability in eukaryotes and improve our understanding of the consequences of ploidy changes and their relevance for disease.

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Rad52 function prevents chromosome loss and truncation in Candida albicans

Cited by 28 publications

References 92 publications

A FACS-Optimized Screen Identifies Regulators of Genome Stability in Candida albicans

A FACS-Optimized Screen Identifies Regulators of Genome Stability in Candida albicans

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

Ploidy changes and genome stability in yeast

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