Dr. Mihailo Mirkovic
Senior Lecturer
mihailo.mirkovic@universityofgalway.ie
Welcome Trust Career Development Award

Research interests

  • Mitosis
  • Chromosome Instability
  • Introns
  • Aneuploidy
  • Adaptation through aneuploidy

Research overview

We study how fungi exploit Chromosome Instability (CIN) to adapt to stress.  Mistakes during mitosis result in CIN and unbalanced, aneuploid karyotypes. In most contexts, aneuploidy lowers cell fitness. However, in fungi, CIN and aneuploidy can be beneficial during stress. Aneuploid karyotypes can survive diverse stress conditions, from elevated temperatures to antifungal treatment, pointing to CIN as a driver of adaptation. Intriguingly, the rate of CIN is elevated in stress, opening the possibility that cells have pathways to destabilize their genomes and accelerate adaptation.

An example of Chromosome Instability (CIN) in budding yeast. Chromosome II is directly visualized using a Chr II Tet-O array and expression of TetR-GFP that binds to the array. In normal mitosis (top), chromosomes are partitioned symmetrically between the mother and daughter cell. In the case of chromosome instability (CIN), both copies (marked by a clustered, single, brighter foci) end up either in the mother or the daughter cell, generating unbalanced, aneuploid karyotypes (Adapted from Mirkovic et al 2025).

Using Saccharomyces cerevisiae and Candida albicans, we will tackle the following questions:

How do cells sense stress and how does this translate into CIN?

Stress results in drastic alteration of pre-mRNA is processing, affecting the function of intron-containing genes. Our previous work has shown that altered pre-mRNA processing and the presence of introns contribute to CIN in ageing. We will explore the role of pre-mRNA processing and introns as drivers of CIN in stress.

Which features of the genome drive elevated CIN?

While the plasticity of fungal genomes during stress is well documented, the drivers are poorly understood. Using the power of genome-wide screens in fungi, we will discover the drivers of CIN in different stress conditions.

Is instability a feature, rather than a bug?

Discovering pathways responsible for CIN in stress allows us to directly test its role in adaptation, by manipulating CIN rates. If instability is required for adaptation, elevated CIN could be a stress response, rather than a “mistake”.

Elevated CIN in stress could be a selected trait, not an error. Cells which can induce instability have higher karyotype variance in stress, allowing them to generate aneuploid karyotypes which can survive the stress (top). If there is no elevated CIN (bottom), there is less variance, and less potential for adaptation.

Key Research Techniques

  • Microscopy
  • Genome editing
  • Yeast genetics
  • Genome-wide screens

Keywords

Mitosis; Introns; RNA processing; Adaptation; Chromosome Instability; Yeast; Antifungal resistance; Aneuploidy

Selected Publications

Most Recent Publications

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Get in Touch!

mihailo.mirkovic@universityofgalway.ie