Chromosome copies confer resistance

Extra copies of key chromosomal segments make Candida fungi drug resistant, could provide cancer clues

By | July 24, 2006

Abnormal chromosomes may underlie fungal resistance to antimicrobials, according to a report in this week's Science. The researchers found that strains of drug-resistant Candida albicans commonly have extra copies of a chromosomal region containing genes that boost resistance. Understanding the formation of these extra chromosomal copies, known as isochromosomes, has implications outside of fungal drug resistance, said senior author Judith Berman of the University of Minnesota. "Isochromosomes form a lot in cancer cells and in other diseases in humans," she told The Scientist. "We think that Candida might be a really nice model for studying some of these rearrangements." C. albicans infections, which are especially problematic in immune-compromised people, are often treated with antifungal drugs called azoles. Fungi become resistant to azoles after long-term exposure to the drugs. Previous work has shown that resistance is sometimes associated with C. albicans mutations that affect drug targets, or increase the activity of proteins that pump drugs out of the cell. Led by Anna Selmecki of the University of Minnesota in Minneapolis-St. Paul, the researchers analyzed gene copy number in azole-sensitive and -resistant strains of C. albicans. Out of 70 strains, they found 23 with abnormal numbers of chromosomes, and that this aneuploidy was seven times as common in drug-resistant strains. Aneuploidy was most prevalent at C. albicans chromosome 5 of azole-resistant strains. They often had an isochromosome -- two identical chromosome arms on either side of the centromere. "It becomes like a mirror image of itself," said Berman. Some strains had this isochromosome instead of one of the normal copies of chromosome 5, while other strains had two normal copies of chromosome 5, plus the isochromosome attached to the end of one of the normal copies. The researchers found that the isochromosomes associated with azole resistance always had two copies of the left chromosome arm, never the right arm. Several genes found on chromosome 5's left arm may explain why extra copies of these genes lead to azole resistance, Berman said: one encodes the azole drug target, and others code for proteins that help pump drugs out of the fungal cell. With extra copies of these genes, a C. albicans strain may be able to remove azole more efficiently, Berman explained. "We've known some genes that are important for drug resistance for a long time, and we knew that they were on chromosome 5," said Ted White of the Seattle Biomedical Research Institute, who wasn't involved in the study. But this study "provides a strong molecular basis for [those] observations," he said. "There are a lot of previous studies indicating that the genome of Candida albicans is fairly plastic and that there are genome rearrangements," said Joseph Heitman of Duke University, who was not involved in the study. But it wasn't suspected "that there would be such a specific example implicated in drug resistance," Heitman said. The chromosomal dynamics that lead to isochromosome formation are also of interest, Heitman said -- especially those that lead to the isochromosome's fusion at the telomere of a normal chromosome. "How that chromosome survives is completely mysterious," he said. The isochromosome mechanism "is very novel and provides a nice example in which the genome plasticity of Candida is tied to in vivo selection," Heitman told The Scientist. "This is evolution in action." Melissa Lee Phillips Links within this article S.P. Hoffert, "Companies seeking solutions to emerging drug resistance," The Scientist, April 13, 1998. A. Selmecki et al., "Aneuploidy and isochromosome formation in drug-resistant Candida albicans," Science, July 21, 2006. Judith Berman T.C. White et al., "Resistance mechanisms in clinical isolates of Candida albicans," Antimicrobial Agents and Chemotherapy, June 2002. PM_ID: 12019079 J.B. Anderson et al., "Mode of selection and experimental evolution of antifungal drug resistance in Saccharomyces cerevisiae," Genetics, April 2003. PM_ID: 12702675 A. Coste et al., "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," Genetics, April 2006. PM_ID: 16452151 D. Steinberg, "Appraising aneuploidy as a cancer cause," The Scientist, March 15, 2004. Ted White Joseph Heitman


Avatar of: David Bump

David Bump

Posts: 15

July 26, 2006

Let's see, every time we expose this type of fungus to this stimuli/threat, it responds in this way. \n\nI would title this, Is this really "evolution in action" or a designed, built-in mechanism for survival?

August 3, 2006

In reference to the article ?Chromosome copies confer resistance? by Melissa Lee Phillips, we wish to bring to your attention that the first report on aneuploidy of a specific chromosome conferring resistance to fluconazole in the human opportunistic pathogen Candida albicans, was published by V. Perepnikhatka, F. J. Fisher, M. Niimi, R. A. Baker, R. D. Cannon, Y.-K. Wang, F. Sherman and E. Rustchenko (Specific chromosomal alterations in fluconazole-resistant mutants of Candida albicans. J. Bacteriol. 181, 4041-4049 [1999]). In this paper, we established for the first time that either diminution of chromosome 4 or a combination of chromosome 4 diminution and chromosome 3 duplication conveys the resistance. This control represented a novel mechanism, which did not involve either the gene ERG11, a target of fluconazole, or the genes for cellular pumps that reside on chromosome 5. Our publication was part of a more general effort being used to demonstrate that C. albicans uses changes in copy number of specific chromosomes to survive in specific adverse environments. Our results on C. albicans survival on a toxic sugar L-sorbose, non-utilized sugar D-arabinose, as well as toxic 5-fluoro-orotic acid and fluconazole, were presented in numerous experimental and review papers. In fact, Dr. J. Berman cited the paper by Perepnikhatka et al. in her review ?Candida albicans: a molecular revolution built on lessons from budding yeast? (J. Berman and P. E. Sudbery, 2002, Nature Reviews Genetics 3: 918-930), but failed to acknowledged our pioneering publication in her current paper. Although, our paper by Perepnikhatka et al. was not cited in "Aneuploidy and isochromosome formation in drug-resistant Candida albicans" (A. Selmecki, A. Forche, J. Berman, 2006, Science 313: 367-370), it is satisfying to know that another laboratory confirmed the relationship between aneuploidy and the resistance to fluconazole.

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