The dual function gene RAD23 contributes to Cryptococcus neoformans virulence independently of its role in nucleotide excision DNA repair

Verma, Surbhi; Shakya, Viplendra P. S.; Idnurm, Alexander

doi:10.1016/j.gene.2019.144043

Cited by 6 publications

(4 citation statements)

References 46 publications

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“…Since Rad23 interacts with Rad4 in vivo, the different levels of cell virulence could represent an independent role of Rad23 itself. Recently, a study in Cryptococcus neoformans revealed that RAD23 regulates cell virulence independent of its role in nucleotide excision DNA repair, which may support our finding in C. albicans (37). Consistent with this, overexpression of RAD23 resulted in increased sensitivity to UV but had no impact on virulence, further supporting the idea that cell virulence regulation by Rad23 may be separate from its role in nuclear damage excision.…”

Section: Discussionsupporting

confidence: 87%

Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

Feng

Yao

Dong

et al. 2020

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In the pathogenic yeast Candida albicans, the DNA damage response contributes to pathogenicity by regulating cell morphology transitions and maintaining survival in response to DNA damage induced by reactive oxygen species (ROS) in host cells. However, the function of nucleotide excision repair (NER) in C. albicans has not been extensively investigated. To better understand the DNA damage response and its role in virulence, we studied the function of the Rad23 nucleotide excision repair protein in detail. The RAD23 deletion strain and overexpression strain both exhibit UV sensitivity, confirming the critical role of RAD23 in the nucleotide excision repair pathway. Genetic interaction assays revealed that the role of RAD23 in the UV response relies on RAD4 but is independent of RAD53, MMS22, and RAD18. RAD4 and RAD23 have similar roles in regulating cell morphogenesis and biofilm formation; however, only RAD23, but not RAD4, plays a negative role in virulence regulation in a mouse model. We found that the RAD23 deletion strain showed decreased survival in a Candida-macrophage interaction assay. Transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) data further revealed that RAD23, but not RAD4, regulates the transcription of a virulence factor, SUN41, suggesting a unique role of RAD23 in virulence regulation. Taking these observations together, our work reveals that the RAD23related nucleotide excision pathway plays a critical role in the UV response but may not play a direct role in virulence. The virulence-related role of RAD23 may rely on the regulation of several virulence factors, which may give us further understanding about the linkage between DNA damage repair and virulence regulation in C. albicans. IMPORTANCE Candida albicans remains a significant threat to the lives of immunocompromised people. An understanding of the virulence and infection ability of C. albicans cells in the mammalian host may help with clinical treatment and drug discovery. The DNA damage response pathway is closely related to morphology regulation and virulence, as well as the ability to survive in host cells. In this study, we checked the role of the nucleotide excision repair (NER) pathway, the key repair system that functions to remove a large variety of DNA lesions such as those caused by UV light, but whose function has not been well studied in C. albicans. We found that Rad23, but not Rad4, plays a role in virulence that appears independent of the function of the NER pathway. Our research revealed that the NER pathway represented by Rad4/Rad23 may not play a direct role in virulence but that Rad23 may play a unique role in regulating the transcription of virulence genes that may contribute to the virulence of C. albicans. KEYWORDS Candida albicans, Rad23, Rad4, nucleotide excision repair, virulence C andida albicans, whose pathogenicity is related to characteristics such as adhesion to and invasion into host cells, the secretion of hydrolases, the yeast-to-hyphal transition, contact sensing and thigmotrop...

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Section: Discussionsupporting

confidence: 87%

Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

Feng

Yao

Dong

et al. 2020

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“…Therefore, the decrease in cytochrome c oxidase in male worms from SCID mice probably results in attenuated energy metabolism and supply and increased apoptosis and finally manifests as developmental retardation or defects (Baden et al, 2007;Hatakeyama and Goto, 2017). In addition, the increase in UV excision repair protein RAD23, which is a nucleotide excision repair protein and plays an important role in nucleotide excision DNA repair through the ubiquitin-proteasome pathway when the genetic material is damaged by UV irradiation or other genotoxic stresses (Mueller and Smerdon, 1996;Schauber et al, 1998;Xie et al, 2004;Gong et al, 2006;Dantuma et al, 2009;Wade et al, 2009;Zhou et al, 2015;Lahari et al, 2017;Verma et al, 2019), also indicates potential genotoxic stresses (or unfavorable living environments) exerted by the hemato-microenvironment of SCID mice on the worms.…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptome Analyses of Schistosoma japonicum Derived From SCID Mice and BALB/c Mice: Clues to the Abnormality in Parasite Growth and Development

Liu¹,

Cheng²,

Ye³

et al. 2020

Front. Microbiol.

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Frontiers in Microbiology | www.frontiersin.org March 2020 | Volume 11 | Article 274 Liu et al.Transcriptome Analysis of S. japonicum From Mice expression profiles of schistosomes from SCID mice when compared with those from BALB/c mice, which were potentially involved in regulating the growth and development of schistosomes. These findings contributed to an understanding of parasite biology and provided a rich resource for the exploitation of antischistosomal intervention targets.

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“…In the wax moth ( Galleria mellonella ) larvae infection model, the UBA2 domain is required for virulence and the XPCB domain is not involved in fungal virulence in C. neoformans , indicating that the role of Rad23 in virulence is also due to its function in protein turnover rather than NER. How the ubiquitin receptor Rad23 regulates virulence remains to be understood ( Verma et al., 2019 ).…”

Section: Ubiquitin Receptorsmentioning

confidence: 99%

More Than Just Cleaning: Ubiquitin-Mediated Proteolysis in Fungal Pathogenesis

Cao

Xue

2021

Front. Cell. Infect. Microbiol.

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Ubiquitin-proteasome mediated protein turnover is an important regulatory mechanism of cellular function in eukaryotes. Extensive studies have linked the ubiquitin-proteasome system (UPS) to human diseases, and an array of proteasome inhibitors have been successfully developed for cancer therapy. Although still an emerging field, research on UPS regulation of fungal development and virulence has been rapidly advancing and has generated considerable excitement in its potential as a target for novel drugs. In this review, we summarize UPS composition and regulatory function in pathogenic fungi, especially in stress responses, host adaption, and fungal pathogenesis. Emphasis will be given to UPS regulation of pathogenic factors that are important for fungal pathogenesis. We also discuss future potential therapeutic strategies for fungal infections based on targeting UPS pathways.

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The dual function gene RAD23 contributes to Cryptococcus neoformans virulence independently of its role in nucleotide excision DNA repair

Cited by 6 publications

References 46 publications

Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

Comparative Transcriptome Analyses of Schistosoma japonicum Derived From SCID Mice and BALB/c Mice: Clues to the Abnormality in Parasite Growth and Development

More Than Just Cleaning: Ubiquitin-Mediated Proteolysis in Fungal Pathogenesis

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