Metabolism‐induced oxidative stress and DNA damage selectively trigger genome instability in polyploid fungal cells

Thomson, Gregory J.; Hernon, Claire; Austriaco, Nicanor; Shapiro, Rebecca; Belenky, Peter; Bennett, Richard J.

doi:10.15252/embj.2019101597

Cited by 50 publications

(46 citation statements)

References 87 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We propose that the host environment is inherently stressful and drives genome instability in C. albicans similarly to stressinduced mutagenesis. There are several physiologically relevant stressors that elevate LOH rates in vitro, including high temperature and oxidative stress (17,41). Reactive oxygen species (ROS) production is an innate immune defense used to defend the host against invading pathogens (7,8), which inhibits growth by inducing DNA damage (42).…”

Section: Discussionmentioning

confidence: 99%

Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States

Smith

Hickman

2020

mSphere

View full text Add to dashboard Cite

Candida albicans is an opportunistic fungal pathogen of humans that is typically diploid yet has a highly labile genome tolerant of large-scale perturbations including chromosomal aneuploidy and loss-of-heterozygosity events. The ability to rapidly generate genetic variation is crucial for C. albicans to adapt to changing or stressful environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, in which tetraploids arise via diploid mating or stress-induced mitotic defects and undergo nonmeiotic ploidy reduction. However, it remains largely unknown how genetic background contributes to C. albicans genome instability in vitro or in the host environment. Here, we tested how genetic background, ploidy, and the host environment impacts C. albicans genome stability. We found that host association induced both loss-of-heterozygosity events and genome size changes, regardless of genetic background or ploidy. However, the magnitude and types of genome changes varied across C. albicans strain background and ploidy state. We then assessed if host-induced genomic changes resulted in fitness consequences on growth rate and nonlethal virulence phenotypes and found that many host-derived isolates significantly changed relative to their parental strain. Interestingly, diploid host-associated C. albicans predominantly decreased host reproductive fitness, whereas tetraploid host-associated C. albicans increased host reproductive fitness. Together, these results are important for understanding how host-induced genomic changes in C. albicans alter its relationship with the host. IMPORTANCE Candida albicans is an opportunistic fungal pathogen of humans. The ability to generate genetic variation is essential for adaptation and is a strategy that C. albicans and other fungal pathogens use to change their genome size. Stressful environments, including the host, induce C. albicans genome instability. Here, we investigated how C. albicans genetic background and ploidy state impact genome instability, both in vitro and in a host environment. We show that the host environment induces genome instability, but the magnitude depends on C. albicans genetic background. Furthermore, we show that tetraploid C. albicans is highly unstable in host environments and rapidly reduces in genome size. These reductions in genome size often resulted in reduced virulence. In contrast, diploid C. albicans displayed modest host-induced genome size changes, yet these frequently resulted in increased virulence. Such studies are essential for understanding how opportunistic pathogens respond and potentially adapt to the host environment.

show abstract

Section: Discussionmentioning

confidence: 99%

Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States

Smith

Hickman

2020

mSphere

View full text Add to dashboard Cite

show abstract

“…Conjugation of opaque a and α cells (heterothallic mating) generates tetraploid a/α cells that are less virulent and less competitive than diploid cells in a model of systemic infection [40]. Recent profiling studies revealed few transcriptional differences between C. albicans diploid and tetraploid cells [44], similar to the analysis of S. cerevisiae cells of differing ploidy [45,46].…”

Section: Mating Ploidy Shifts and Aneuploidymentioning

confidence: 87%

The Impact of Gene Dosage and Heterozygosity on the Diploid Pathobiont Candida albicans

Liang

Bennett

2019

JoF

Self Cite

View full text Add to dashboard Cite

Candida albicans is a fungal species that can colonize multiple niches in the human host where it can grow either as a commensal or as an opportunistic pathogen. The genome of C. albicans has long been of considerable interest, given that it is highly plastic and can undergo a wide variety of alterations. These changes play a fundamental role in determining C. albicans traits and have been shown to enable adaptation both to the host and to antifungal drugs. C. albicans isolates contain a heterozygous diploid genome that displays variation from the level of single nucleotides to largescale rearrangements and aneuploidy. The heterozygous nature of the genome is now increasingly recognized as being central to C. albicans biology, as the relative fitness of isolates has been shown to correlate with higher levels of overall heterozygosity. Moreover, loss of heterozygosity (LOH) events can arise frequently, either at single polymorphisms or at a chromosomal level, and both can alter the behavior of C. albicans cells during infection or can modulate drug resistance. In this review, we examine genome plasticity in this pathobiont focusing on how gene dosage variation and loss of heterozygosity events can arise and how these modulate C. albicans behavior.

show abstract

“…29 Aberrant oxidative regulation has been observed in various types of cancer cells. 30,31 Mounting evidence indicates that perturbation of oxidative homeostasis is involved in tumorigenesis. 32,33 However, the roles of antioxidant molecules in malignant cancers, especially liver cancer, are relatively unclear.…”

Section: Discussionmentioning

confidence: 99%

SRXN1 stimulates hepatocellular carcinoma tumorigenesis and metastasis through modulating ROS/p65/BTG2 signalling

Zhang

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Sulfiredoxin 1 (SRXN1) is a pivotal regulator of the antioxidant response in eukaryotic cells. However, the role of SRXN1 in hepatocellular carcinoma (HCC) is far from clear. The present study aims to elucidate whether SRXN1 participates in tumorigenesis and metastasis of HCC and to determine the molecular mechanisms. We found that SRXN1 expression was up‐regulated in HCC tissue samples and correlated with poor prognosis in HCC patients. We also observed that SRXN1 knockdown by transient siRNA transfection inhibited HCC cell proliferation, migration and invasion. Overexpression of SRXN1 increased HCC cell migration and invasion. B‐cell translocation gene 2 (BTG2) was identified as a downstream target of SRXN1. Mechanistic studies revealed that SRXN1‐depleted reactive oxygen species (ROS) modulated migration and invasion of HCC cells. In addition, the ROS/p65/BTG2 signalling hub was found to regulate the epithelial‐mesenchymal transition (EMT), which mediates the pro‐metastasis role of SRXN1 in HCC cells. In vivo experiments showed SRXN1 promotes HCC tumour growth and metastasis in mouse subcutaneous xenograft and metastasis models. Collectively, our results revealed a novel pro‐tumorigenic and pro‐metastatic function of SRXN1 in HCC. These findings demonstrate a rationale to exploit SRXN1 as a therapeutic target effectively preventing metastasis of HCC.

show abstract

Metabolism‐induced oxidative stress and DNA damage selectively trigger genome instability in polyploid fungal cells

Cited by 50 publications

References 87 publications

Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States

Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States

The Impact of Gene Dosage and Heterozygosity on the Diploid Pathobiont Candida albicans

SRXN1 stimulates hepatocellular carcinoma tumorigenesis and metastasis through modulating ROS/p65/BTG2 signalling

Contact Info

Product

Resources

About