Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans
ABSTRACT DNA polymerase ε (Polε) is an essential replicative polymerase consisting of Pol2, Dpb2, Dpb3, and Dpb4 subunits and has not been explored in the pathogenic yeast Candida albicans. C. albicans is accountable for >40% of deaths due to systemic candidiasis per year worldwide. Genome plasti...
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American Society for Microbiology
2024-10-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01227-24 |
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| author | Bhabasha Gyanadeep Utkalaja Shraddheya Kumar Patel Satya Ranjan Sahu Abinash Dutta Narottam Acharya |
| author_facet | Bhabasha Gyanadeep Utkalaja Shraddheya Kumar Patel Satya Ranjan Sahu Abinash Dutta Narottam Acharya |
| author_sort | Bhabasha Gyanadeep Utkalaja |
| collection | DOAJ |
| description | ABSTRACT DNA polymerase ε (Polε) is an essential replicative polymerase consisting of Pol2, Dpb2, Dpb3, and Dpb4 subunits and has not been explored in the pathogenic yeast Candida albicans. C. albicans is accountable for >40% of deaths due to systemic candidiasis per year worldwide. Genome plasticity is one of the adaptive mechanisms associated with virulence, and as it is associated with DNA polymerase function, this study explored the role of Polε in genome stability and pathogenesis of C. albicans. POL2 and DPB2 are haploinsufficient, but DPB3 and DPB4 are dispensable for cell survival in diploid C. albicans. However, unlike in Saccharomyces cerevisiae, loss of any or both of the nonessential subunits or defective interaction between the two resulted in slow growth and temperature-sensitive phenotypes. Knockout strains of C. albicans (dpb3ΔΔ and dpb4ΔΔ and dpb3ΔΔdpb4ΔΔ) also exhibited sensitivity to genotoxic agents and delayed cell cycle progression. Reduced processive DNA synthesis and increased rate of mutagenesis were observed in dpb3 and dpb4 null strains. Whole-genome sequencing further confirmed the accumulation of indels and SNPs majorly in the intergenic repeat regions of the chromosomes of dpb3ΔΔdpb4ΔΔ. Polε-defective strains were constitutively filamentous and non-pathogenic in mice models of systemic candidiasis. Altogether, this study showed that the function of the Dpb3-Dpb4 subcomplex is critical for fungal morphogenesis and virulence besides its role as a structural component of Polε in DNA replication and genome stability; thus, their interacting interface may be targeted to develop antifungal drugs.IMPORTANCEThis study explored the role of DNA polymerase epsilon, especially its non-essential structural subunits in Candida albicans biology. Apart from their role in DNA replication and genome stability, the Dpb3-Dpb4 subcomplex regulates morphological switching and virulence. Since the defective strain is locked in filamentous form and is avirulent, the complex may be targeted for anti-fungal drug development. |
| format | Article |
| id | doaj-art-7a65ca77fdbf43d880b232a912af2f3a |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-7a65ca77fdbf43d880b232a912af2f3a2025-08-20T02:17:06ZengAmerican Society for MicrobiologymBio2150-75112024-10-01151010.1128/mbio.01227-24Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicansBhabasha Gyanadeep Utkalaja0Shraddheya Kumar Patel1Satya Ranjan Sahu2Abinash Dutta3Narottam Acharya4Laboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaLaboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaABSTRACT DNA polymerase ε (Polε) is an essential replicative polymerase consisting of Pol2, Dpb2, Dpb3, and Dpb4 subunits and has not been explored in the pathogenic yeast Candida albicans. C. albicans is accountable for >40% of deaths due to systemic candidiasis per year worldwide. Genome plasticity is one of the adaptive mechanisms associated with virulence, and as it is associated with DNA polymerase function, this study explored the role of Polε in genome stability and pathogenesis of C. albicans. POL2 and DPB2 are haploinsufficient, but DPB3 and DPB4 are dispensable for cell survival in diploid C. albicans. However, unlike in Saccharomyces cerevisiae, loss of any or both of the nonessential subunits or defective interaction between the two resulted in slow growth and temperature-sensitive phenotypes. Knockout strains of C. albicans (dpb3ΔΔ and dpb4ΔΔ and dpb3ΔΔdpb4ΔΔ) also exhibited sensitivity to genotoxic agents and delayed cell cycle progression. Reduced processive DNA synthesis and increased rate of mutagenesis were observed in dpb3 and dpb4 null strains. Whole-genome sequencing further confirmed the accumulation of indels and SNPs majorly in the intergenic repeat regions of the chromosomes of dpb3ΔΔdpb4ΔΔ. Polε-defective strains were constitutively filamentous and non-pathogenic in mice models of systemic candidiasis. Altogether, this study showed that the function of the Dpb3-Dpb4 subcomplex is critical for fungal morphogenesis and virulence besides its role as a structural component of Polε in DNA replication and genome stability; thus, their interacting interface may be targeted to develop antifungal drugs.IMPORTANCEThis study explored the role of DNA polymerase epsilon, especially its non-essential structural subunits in Candida albicans biology. Apart from their role in DNA replication and genome stability, the Dpb3-Dpb4 subcomplex regulates morphological switching and virulence. Since the defective strain is locked in filamentous form and is avirulent, the complex may be targeted for anti-fungal drug development.https://journals.asm.org/doi/10.1128/mbio.01227-24Candida albicansDNA replicationDNA polymerasewhole genome sequencingsystemic candidiasisvirulence |
| spellingShingle | Bhabasha Gyanadeep Utkalaja Shraddheya Kumar Patel Satya Ranjan Sahu Abinash Dutta Narottam Acharya Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans mBio Candida albicans DNA replication DNA polymerase whole genome sequencing systemic candidiasis virulence |
| title | Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans |
| title_full | Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans |
| title_fullStr | Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans |
| title_full_unstemmed | Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans |
| title_short | Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans |
| title_sort | critical roles of dpb3 dpb4 sub complex of dna polymerase epsilon in dna replication genome stability and pathogenesis of candida albicans |
| topic | Candida albicans DNA replication DNA polymerase whole genome sequencing systemic candidiasis virulence |
| url | https://journals.asm.org/doi/10.1128/mbio.01227-24 |
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