CHAC2 is essential for self-renewal and glutathione maintenance in human embryonic stem cells

Wang, Cheng-Kai; Yang, Shan-Yi; Hsu, Shu-Shong; Chang, Fang-Pei; Lin, Ying-Zu; Chen, Shang‐Fu; Cheng, Chin-Lun; Hsiao, Michael; Lu, Frank Leigh; Lu, Jean

doi:10.1016/j.freeradbiomed.2017.10.345

Cited by 34 publications

(29 citation statements)

References 41 publications

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“…After 1 h of reaction, ChaC1 degraded 99.14% of the total GSH; however, ChaC2 was unable to degrade GSH as efficiently as ChaC1. ChaC2 was only able to degrade 58.97% of the total GSH ( Figure 6B), which is consistent with the previously reported results [10,13]. ChaC2 E74Q and ChaC2 E83Q exhibited lower GSH degradation activity than ChaC2, that is, 21.34% and 27.15% degradation of the total GSH, respectively ( Figure 6B).…”

Section: Chac2 E74q and Chac2 E83q Mutations Significantly Reduced Gssupporting

confidence: 91%

“…These results indicate that ChaC2 modulates the growth of breast cancer cells via its GSH degradation activity in the GSH metabolism. ChaC2 knockdown has been shown to downregulate Nrf2, a master of the antioxidant response [10]. In breast cancer cells, Nrf2 has been also shown to be overexpressed and promote cell proliferation [51,52].…”

Section: Correlation Of Chac2 Gsh Degradation and Breast Cancermentioning

confidence: 99%

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Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

et al. 2019

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Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

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Section: Chac2 E74q and Chac2 E83q Mutations Significantly Reduced Gssupporting

confidence: 91%

Section: Correlation Of Chac2 Gsh Degradation and Breast Cancermentioning

confidence: 99%

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

et al. 2019

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“…Therefore, human PSCs have emerged as a promising cell resource for regenerative medicine and a particular experimental model [26]. Accumulated evidence from studies of hESCs suggests that the self‐renewal of ESCs was regulated via ROS to a certain degree [27,28]. Meanwhile, a previous study indicated that stem cells were highly susceptible to DNA damage and cause DNA damage accumulation in the microenvironment of growing stem cells, which was partly responsible for catastrophic consequences for tissue and body homeostasis [29].…”

Section: Discussionmentioning

confidence: 99%

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

Han

Chen

et al. 2020

FEBS Open Bio

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Iron overload affects the cell cycle of various cell types, but the effect of iron overload on human pluripotent stem cells has not yet been reported. Here, we show that the proliferation capacities of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) were significantly inhibited by ferric ammonium citrate (FAC) in a concentration‐dependent manner. In addition, deferoxamine protected hESCs/hiPSCs against FAC‐induced cell‐cycle arrest. However, iron overload did not affect pluripotency in hESCs/hiPSCs. Further, treatment of hiPSCs with FAC resulted in excess reactive oxygen species production and DNA damage. Collectively, our findings provide new insights into the role of iron homeostasis in the maintenance of self‐renewal in human pluripotent stem cells.

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“…Sixth, a very strong colocalized trans -eQTL for CHAC2 was identified at INHBB. CHAC2 is a y-glutamyl cyclotransferase involved in glutathione homeostasis [42, 43]. Proximal tubule cells contain high levels of glutathione which is transported in and out of the kidney via OAT1/3, MRP2/4 and OAT10 [44, 45].…”

Section: Discussionmentioning

confidence: 99%

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Boocock

Leask

Okada

et al. 2019

Preprint

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69Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of 70 gout and a predictor of renal disease, cardiovascular disease and other metabolic 71 conditions. Genome-wide association studies (GWAS) have reported dozens of loci 72 associated with serum urate control, however there has been little progress in 73 understanding the molecular basis of the associated loci. Here we employed trans-74 ancestral meta-analysis using data from European and East Asian populations to 75 identify ten new loci for serum urate levels. Genome-wide colocalization with cis-76 expression quantitative trait loci (eQTL) identified a further five new loci. By cis-and 77 trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where 78 the causal eQTL variant has a high likelihood that it is shared with the serum urate-79 associated locus. One new locus identified was SLC22A9 that encodes organic anion 80 transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate 81 exchanger. Newly implicated genes identified in the eQTL analysis include those 82 encoding proteins that make up the dystrophin complex, a scaffold for signaling 83 proteins and transporters at the cell membrane; MLXIP that, with the previously 84 identified MLXIPL, is a transcription factor that may regulate serum urate via the 85 pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for 86 mitochondrial function. Trans-ancestral functional fine-mapping identified six loci 87 (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that 88 contained putative causal SNPs (posterior probability of causality > 0.8). This 89 systematic analysis of serum urate GWAS loci has identified candidate causal genes at 90 19 loci and a network of previously unidentified genes likely involved in control of 91 serum urate levels, further illuminating the molecular mechanisms of urate control. 92 93 Author Summary 94 High serum urate is a prerequisite for gout and a risk factor for metabolic disease. 95Previous GWAS have identified numerous loci that are associated with serum urate 96 control, however, only a small handful of these loci have known molecular 97 consequences. The majority of loci are within the non-coding regions of the genome 98 and therefore it is difficult to ascertain how these variants might influence serum urate 99 levels without tangible links to gene expression and / or protein function. We have 100 applied a novel bioinformatic pipeline where we combined population-specific GWAS 101 4 data with gene expression and genome connectivity information to identify putative 102 causal genes for serum urate associated loci. Overall, we identified 15 novel serum 103 urate loci and show that these loci along with previously identified loci are linked to 104 the expression of 44 genes. We show that some of the variants within these loci have 105 strong predicted regulatory function which can be further tested in functional analyses. 106 This study expands on previous GWAS by ident...

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CHAC2 is essential for self-renewal and glutathione maintenance in human embryonic stem cells

Cited by 34 publications

References 41 publications

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

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