Histone H4 dosage modulates DNA damage response in the pathogenic yeast Candida glabrata via homologous recombination pathway

Kumar, Kundan; Moirangthem, Romila; Kaur, Rupinder

doi:10.1371/journal.pgen.1008620

Cited by 14 publications

(24 citation statements)

References 58 publications

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“…For example, Candida glabrata is not only the second most common cause of invasive candidiasis of skin, mucosa and even viscera but also accounts for up to 30% of Candida bloodstream infections. 29 Candida parapsilosis is the second or third most frequently isolated Candida species from patients with invasive candidiasis. 27 Cladosporium species were reported to cause various super cial and invasive fungal infections, such as brain abscess and keratitis.…”

Section: Discussionmentioning

confidence: 99%

Gut mycobiota alterations in patients with COVID-19 and H1N1 and associations with immune and gastrointestinal symptoms

Jiang

et al. 2020

Preprint

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The relationship between gut microbes and COVID-19 or H1N1 flu is not fully understood. Here, we compared gut mycobiota of 67 COVID-19 patients, 35 H1N1 patients and 48 healthy controls (HCs) using internal transcribed spacer (ITS) 3-ITS4 sequencing. Fungal richness decreased in COVID-19 and H1N1 patients compared to HCs, but fungal diversity decreased in only H1N1 patients. Fungal mycobiota dysbiosis in both COVID-19 and H1N1 patients was mainly characterized by depletions of fungi such as Aspergillus, Penicillium, but several fungi, such as Candida parapsilosis, and Malassezia yamatoensis, were enriched in H1N1 patients. The altered fungal taxa were strongly associated with clinical features such as the incidence of diarrhoea, albumin. Gut mycobiota between COVID-19 patients with mild and severity symptoms are not different, as well as between COVID-19 patients in and out hospital. Therefore, gut mycobiota dysbiosis occur in covid-19 or H1N1 patients and do not improve until discharge.

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Section: Discussionmentioning

confidence: 99%

Gut mycobiota alterations in patients with COVID-19 and H1N1 and associations with immune and gastrointestinal symptoms

Jiang

et al. 2020

Preprint

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“…Recently, MMS exposure was found to cause significant reduction in mRNA and protein amounts of both H3 and H4 histones in the pathogenic yeast C. glabrata , with low H4 gene dosage also giving rise to MMS resistance (Kumar et al 2020 ). In this study, we had shown a requirement for HR in the repair of MMS-induced DNA damage, and low H4 levels resulting in increased HR efficiency, faster repair of damaged DNA and MMS resistance (Kumar et al 2020 ). However, this MMS resistance was specific to the loss of two H4-encoding genes, probably due to the H4 amount produced by the remaining H4 ORF (Kumar et al 2020 ).…”

Section: Histones and Dna Damagementioning

confidence: 99%

“…However, this MMS resistance was specific to the loss of two H4-encoding genes, probably due to the H4 amount produced by the remaining H4 ORF (Kumar et al 2020 ). C. glabrata contains three histone H4 genes, CgHHF1, 2 and 3 , with CgHHF1 and 2 genes exhibiting synteny with their S. cerevisiae counterparts (Kumar et al 2020 ). Of these, while CgHHF1 and 2 gene loss rendered C. glabrata cells resistant to MMS, deletion of CgHHF2 and 3 genes made cells sensitive to MMS (Kumar et al 2020 ), indicating that the deletion of two H4 genes can have opposite biological consequences.…”

Section: Histones and Dna Damagementioning

confidence: 99%

“…C. glabrata contains three histone H4 genes, CgHHF1, 2 and 3 , with CgHHF1 and 2 genes exhibiting synteny with their S. cerevisiae counterparts (Kumar et al 2020 ). Of these, while CgHHF1 and 2 gene loss rendered C. glabrata cells resistant to MMS, deletion of CgHHF2 and 3 genes made cells sensitive to MMS (Kumar et al 2020 ), indicating that the deletion of two H4 genes can have opposite biological consequences. Notably, MMS resistance was not observed in any mutant carrying low dosage of histone H3 genes (Kumar et al 2020 ).…”

Section: Histones and Dna Damagementioning

confidence: 99%

“…Of these, while CgHHF1 and 2 gene loss rendered C. glabrata cells resistant to MMS, deletion of CgHHF2 and 3 genes made cells sensitive to MMS (Kumar et al 2020 ), indicating that the deletion of two H4 genes can have opposite biological consequences. Notably, MMS resistance was not observed in any mutant carrying low dosage of histone H3 genes (Kumar et al 2020 ). Furthermore, reduction in the H4 gene dosage had no significant impact on the transcript abundance of histone H3, while the converse was not always true (Kumar et al 2020 ).…”

Section: Histones and Dna Damagementioning

confidence: 99%

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Genome protection: histone H4 and beyond

2020

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Histone proteins regulate cellular factors’ accessibility to DNA, and histone dosage has previously been linked with DNA damage susceptibility and efficiency of DNA repair pathways. Surplus histones are known to impede the DNA repair process by interfering with the homologous recombination-mediated DNA repair in Saccharomyces cerevisiae. Here, we discuss the recent finding of association of methyl methanesulfonate (MMS) resistance with the reduced histone H4 gene dosage in the pathogenic yeast Candida glabrata. We have earlier shown that while the low histone H3 gene dosage led to MMS susceptibility, the lack of two H4-encoding ORFs, CgHHF1 and CgHHF2, led to resistance to MMS-induced DNA damage. This resistance was linked with a higher rate of homologous recombination (HR). Taking these findings further, we review the interactome analysis of histones H3 and H4 in C. glabrata. We also report that the arginine residue present at the 95th position in the C-terminal tail of histone H4 protein is required for complementation of the MMS resistance in the Cghhf1Δhhf2Δ mutant, thereby pointing out a probable role of this residue in association with HR factors. Additionally, we present evidence that reduction in H4 protein levels may constitute an important part of varied stress responses in C. glabrata. Altogether, we present an overview of histone H4 dosage, HR-mediated repair of damaged DNA and stress resistance in this opportunistic human fungal pathogen.

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GSTpi reduces DNA damage and cell death by regulating the ubiquitination and nuclear translocation of NBS1

Zhou

Shi

et al. 2021

Cell. Mol. Life Sci.

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Glutathione S-transferase pi (GSTpi) is an important phase detoxifying enzyme that participates in various physiological processes, such as antioxidant, detoxi cation, and signal transduction. The high expression level of GSTpi has been reported to be related to drug-resistant and anti-in ammatory and it functioned via its non-catalytic ligandin. However, the previous protection mechanism of GSTpi in DNA damage has not been addressed so far. Nijmegen breakage syndrome 1 (NBS1) is one of the most important sensor proteins to detect damaged DNA. Here, we investigated the interaction between GSTpi and NBS1 in HEK-293T cells and human breast adenocarcinoma cells during DNA damage. Our results showed that overexpression of GSTpi in cells by transfecting DNA vector decreased the DNA damage level after Methyl methanesulfonate (MMS) or Adriamycin (ADR) treatment. We found that cytosolic GSTpi could increase NBS1 ubiquitin-mediated degradation in unstimulated cells, which suggested that GSTpi could maintain the basal level of NBS1 during normal conditions. In response to DNA damage, GSTpi can be phosphorylated in Ser184 and inhibit the ubiquitination degradation of NBS1 mediated by Skp2 to recover NBS1 protein level. Phosphorylated GSTpi can further enhance NBS1 nuclear translocation to activate the ATM-Chk2-p53 signaling pathway. Finally, GSTpi blocked the cell cycle in the G2/M phase to gain more time for cells to repair. Thus, our nding revealed the novel mechanism of GSTpi via its Ser184 phosphorylation to protect cells from cell death during DNA damage and it enriches the function of GSTpi in drug resistance.

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Histone H4 dosage modulates DNA damage response in the pathogenic yeast Candida glabrata via homologous recombination pathway

Cited by 14 publications

References 58 publications

Gut mycobiota alterations in patients with COVID-19 and H1N1 and associations with immune and gastrointestinal symptoms

Gut mycobiota alterations in patients with COVID-19 and H1N1 and associations with immune and gastrointestinal symptoms

Genome protection: histone H4 and beyond

GSTpi reduces DNA damage and cell death by regulating the ubiquitination and nuclear translocation of NBS1

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