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Updated: Apr 1, 2026
Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
The Role of Mms22p in DNA Damage Response in Candida albicans
Lan Yan1, Juan Xiong2, Hui Lu3
1Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China.
Abstract:
To ensure correct DNA replication, eukaryotes have signaling pathways that respond to replication-associated DNA damage and trigger repair. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, a complex of proteins, including the cullin protein Rtt101p and two adapter proteins Mms22p and Mms1p, is important for proper response to replication stress. We have investigated this system in Candida albicans. In this pathogen, Mms22p is important for recovery from DNA replication damage induced by agents including methylmethane sulfonate, camptothecin, and ionizing radiation. Although no clear ortholog of Mms1p has been identified in C. albicans, loss of either Mms22p or Rtt101p generates similar damage sensitivity, consistent with a common function. In S. cerevisiae, the Mrc1p-Csm3p-Tof1p complex stabilizes stalled replication forks and activates a replication checkpoint and interacts with Mms22p. A similar complex in S. pombe, consisting of the Tof1p and Csm3p orthologs Swi1p and Swi3p, along with the fission yeast Mrc1p, genetically also interacts with Mms22p. Intriguingly in C. albicans only Mrc1p and Csm3p appear involved in damage repair, and Mms22p is required for responding to DNA damage agents in MRC1 or CSM3 conditional mutants. In C. albicans, although the loss of RAD57 greatly impairs response in the pathogen to many DNA-damaging agents, lethality due to camptothecin damage requires concomitant loss of Rad57p and Mms22p, suggesting that Mms22p is only essential for homologous recombination induced by camptothecin. These results establish that although C. albicans uses conserved cellular modules to respond to DNA damage and replication blocks, the specific details of these modules differ significantly from the S. cerevisiae model.
Insights
Candida albicans utilizes conserved DNA damage repair pathways, but key protein interactions, like those involving Mms22p, differ from yeast models. This study reveals unique aspects of replication stress response in this fungal pathogen.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Eukaryotes possess signaling pathways to manage DNA replication errors and damage.
- Protein complexes involving Rtt101p, Mms22p, and Mms1p are crucial for replication stress response in yeast.
- Understanding these pathways in pathogenic fungi like Candida albicans is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of DNA replication damage response proteins, specifically Mms22p and Rtt101p, in Candida albicans.
- To compare the DNA damage and replication stress response mechanisms in C. albicans with those in Saccharomyces cerevisiae and Schizosaccharomyces pombe.
Main Methods:
- Investigated the function of Mms22p and Rtt101p in C. albicans using various DNA-damaging agents (methylmethane sulfonate, camptothecin, ionizing radiation).
- Analyzed genetic interactions between Mms22p, Rtt101p, and other conserved proteins like Mrc1p and Csm3p.
- Examined the role of RAD57 in conjunction with Mms22p in response to camptothecin-induced damage.
Main Results:
- Mms22p is essential for C. albicans recovery from DNA replication damage induced by multiple agents.
- While C. albicans shares functional similarities with yeast regarding Rtt101p and Mms22p, a direct Mms1p ortholog is absent.
- Mrc1p and Csm3p are involved in damage repair, with Mms22p's requirement dependent on these proteins under specific conditions.
- The combined absence of Rad57p and Mms22p is lethal under camptothecin-induced damage, indicating Mms22p's specific role in homologous recombination.
Conclusions:
- Candida albicans employs conserved protein modules for DNA damage and replication stress response.
- Significant differences exist in the specific protein interactions and functional details of these pathways compared to the well-studied yeast models.
- Mms22p plays a critical, albeit distinct, role in the DNA repair network of this important fungal pathogen.
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