Hsp90 induces increased genomic instability toward DNA-damaging agents by tuning down<i>RAD53</i>transcription

Khurana, Nidhi; Laskar, Shyamasree; Bhattacharyya, Mrinal Kanti; Bhattacharyya, Sunanda

doi:10.1091/mbc.e15-12-0867

“…7; our model also takes into account that, in C. auris, constitutive pseudohyphal growth is triggered by downregulation of HSP90, a heat shock family protein, which acts as a chaperone and influences a diverse range of signal transducers (48). Inhibition of HSP90 induces pseudohyphal growth via cAMP-PKA signaling in an Efg1-independent way in C. albicans (73), and, interestingly, a direct inhibition of Rad53 by Hsp90 has been observed in S. cerevisiae (74).…”

Section: Discussionmentioning

confidence: 99%

Pseudohyphal Growth of the Emerging Pathogen Candida auris Is Triggered by Genotoxic Stress through the S Phase Checkpoint

Ruiz

¹

,

Ross

²

,

Gow

³

et al. 2020

mSphere

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The morphogenetic switching between yeast cells and filaments (true hyphae and pseudohyphae) is a key cellular feature required for full virulence in many polymorphic fungal pathogens, such as Candida albicans. In the recently emerged yeast pathogen Candida auris, occasional elongation of cells has been reported. However, environmental conditions and genetic triggers for filament formation have remained elusive. Here, we report that induction of DNA damage and perturbation of replication forks by treatment with genotoxins, such as hydroxyurea, methyl methanesulfonate, and the clinically relevant fungistatic 5-fluorocytosine, cause filamentation in C. auris. The filaments formed were characteristic of pseudohyphae and not parallel-sided true hyphae. Pseudohyphal growth is apparently signaled through the S phase checkpoint and, interestingly, is Tup1 independent in C. auris. Intriguingly, the morphogenetic switching capability is strain specific in C. auris, highlighting the heterogenous nature of the species as a whole. IMPORTANCE Candida auris is a newly emerged fungal pathogen of humans. This species was first reported in 2009 when it was identified in an ear infection of a patient in Japan. However, despite intense interest in this organism as an often multidrug-resistant fungus, there is little knowledge about its cellular biology. During infection of human patients, fungi are able to change cell shape from ellipsoidal yeast cells to elongated filaments to adapt to various conditions within the host organism. There are different types of filaments, which are triggered by reactions to different cues. Candida auris fails to form filaments when exposed to triggers that stimulate yeast filament morphogenesis in other fungi. Here, we show that it does form filaments when its DNA is damaged. These conditions might arise when Candida auris cells interact with host immune cells or during growth in certain host tissues (kidney or bladder) or during treatment with antifungal drugs.

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“…Lastly, our study design allowed us to address the controversy whether HSP90-dependent phenotypes are largely a consequence of de novo mutations arising in HSP90-reduced lines as recently argued (22). Although HSP90 inhibition increases the frequency of certain mutations (2,20,21,23,24,(43)(44)(45)(46)(47)(48), we find no evidence that the majority of HSP90-dependent phenotypes observed here arises due to HSP90-dependent de novo mutations. In sum, our results resolve the two remaining controversies surrounding the HSP90 capacitor hypothesis.…”

Section: Introductionmentioning

confidence: 53%

“…RNAi-C1 background is either that these plants were more deeply mutagenized than Col-0 plants or that fewer mutations were repaired. HSP90 chaperones proteins that function in DNA repair (50,51), and as HSP90 inhibition also increases the rate of certain mutations (2,(20)(21)(22)(23)(43)(44)(45)(46)(47)(48), even equivalent EMS treatments may produce more mutations in the HSP90 RNAi-C1 background. Alternatively, as predicted under the capacitor hypothesis (25,31,(52)(53)(54), some EMS-generated mutations may acquire greater penetrance when HSP90 is inhibited and therefore result in embryonic lethality.…”

Section: A Trivial Explanation For the Greater Number Of Embryonic Lementioning

confidence: 99%

HSP90 buffers newly induced mutations in massively mutated plant lines

Mason

¹

,

Carlson

²

,

Press

³

et al. 2018

Preprint

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(300 words)Robustness to both genetic and environmental change is an emergent feature of living systems.Loss of phenotypic robustness can be associated with increased penetrance of genetic variation.In model organisms and in humans, the phenotypic consequences of standing genetic variation can be buffered by the molecular chaperone HSP90. However, it has been argued that HSP90 has the opposite effect on newly introduced genetic variation. To test the buffering effect of HSP90 on new mutations, we introduced vast numbers of mutations into wild-type and HSP90-reduced plants and assessed embryonic lethality and early seedling phenotypes for thousands of offspring. Although the levels of newly introduced mutations were similar in the two backgrounds, the HSP90-reduced plants showed a significantly greater frequency of embryonic

show abstract

“…6; our model also takes into account that, in C. auris, constitutive pseudohyphal growth is triggered by downregulation of HSP90, a heat-shock family protein, which acts as chaperone and influences a diverse range of signal transducers (48). Inhibition of HSP90 induces pseudohyphal growth via cAMP-PKA signalling in an Efg1-independent way in C. albicans (73) and, interestingly, a direct inhibition of Rad53 by Hsp90 has been observed in S. cerevisiae (74).…”

Section: Discussionmentioning

confidence: 99%

Pseudohyphal growth of the emerging pathogenCandida aurisis triggered by genotoxic stress through the S phase checkpoint

Ruiz

¹

,

Ross

²

,

Gow

³

et al. 2019

Preprint

View full text Add to dashboard Cite

The morphogenetic switching between yeast cells and filaments (true hyphae and pseudohyphae) is a key cellular feature required for full virulence in many polymorphic fungal pathogens, such as Candida albicans. In the recently emerged yeast pathogen Candida auris, occasional elongation of cells has been reported. However, environmental conditions and genetic triggers for filament formation have remained elusive. Here, we report that induction of DNA damage and perturbation of replication forks by treatment with genotoxins, such as hydroxyurea, methyl methanesulfonate, and the clinically relevant fungistatic 5-fluorocytosine, causes filamentation in C. auris. The filaments formed were characteristic of pseudohyphae and not parallel-sided true hyphae. Pseudohyphal growth is apparently signalled through the S phase checkpoint and, interestingly, is Tup1-independent in C. auris. Intriguingly, the morphogenetic switching capability is strain-specific in C. auris, highlighting the heterogenous nature of the species as a whole.

show abstract

Hsp90 induces increased genomic instability toward DNA-damaging agents by tuning downRAD53transcription

Cited by 16 publications

References 47 publications

Pseudohyphal Growth of the Emerging Pathogen Candida auris Is Triggered by Genotoxic Stress through the S Phase Checkpoint

Pseudohyphal Growth of the Emerging Pathogen Candida auris Is Triggered by Genotoxic Stress through the S Phase Checkpoint

HSP90 buffers newly induced mutations in massively mutated plant lines

Pseudohyphal growth of the emerging pathogenCandida aurisis triggered by genotoxic stress through the S phase checkpoint

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