Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

Liu, Zhilei; Hu, Yadong; Gong, Yiyi; Zhang, Wenhao; Liu, Chongdong; Wang, Qingtao; Deng, Haiteng

doi:10.1016/j.freeradbiomed.2016.07.030

Cited by 22 publications

(12 citation statements)

References 54 publications

(54 reference statements)

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“…Examination of AGR2 amino acid sequence reveals a single CXXS active domain motif (AA 81 to 84 ) (Figure 1) for oxidation and reduction reactions (17,41), and the N-terminal region (AA 21 to 44) (Figure 1), which is responsible for the cell adhesion properties of AGR2 (18). In addition to being an ER-resident protein, AGR2 is also localized in cytoplasm (58), nucleus (30,33), mitochondria (32), cell surface (12), extracellular matrix (14), and blood and urine (6,13,14), although the mechanism by which AGR2 accesses the cytoplasm, nucleus and extracellularly is unclear.…”

Section: A -Agr2 Is a Multidomain Proteinmentioning

confidence: 99%

The anterior gradient-2 interactome

Delom

Mohtar

Hupp

et al. 2020

American Journal of Physiology-Cell Physiology

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The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

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Section: A -Agr2 Is a Multidomain Proteinmentioning

confidence: 99%

The anterior gradient-2 interactome

Delom

Mohtar

Hupp

et al. 2020

American Journal of Physiology-Cell Physiology

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“…In eukaryotes, two UNG isoforms have been characterized: UNG1 resides in mitochondria and UNG2 in the nucleus. UNG1 is found proximal to the mitochondrial respiratory chain, where ROS are actively generated; therefore, it has received more attention than UNG2 in earlier studies that have explored the mechanisms via which UNG1 help cancer cells to resist ROS (Liu et al 2016). Consequently, the role of UNG2 in therapeutic cellular resistance to ROS and its therapeutic potential, remain elusive until the present study.…”

Section: Uracil-dna N-glycosylase2 (Ung2)-a New Tie That Binds Ros Tomentioning

confidence: 90%

A new insight into base excision repair (BER) in targeted cancer therapy

Kumar

2020

GENOME INSTAB. DIS.

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Dysregulation of redox homeostasis and the resulting generation of excessive reactive oxygen species (ROS) and oxidative DNA damage play an obligatory role in the progression of human cancer as well as therapeutic sensitivity to a variety of genome-targeting cancer drugs. In a recent study, Bao et al. (Free Radic Biol Med, 2020), present a novel mechanism that governs the sensitivity of certain cancer cells to DNA damaging therapies. The authors have identified a novel, ROSassociated, lysine acetylation modification in Uracil-DNA N-glycosylase 2 (UNG2)-a key understudied component of the base excision repair pathway, which primes UNG2 for subsequent ubiquitination by UHRF1 ligase, leading to coupling the UNG2 degradation to cancer cell death in a ROS-sensitive manner. Translational innovation of these mechanistic findings resides by the ability of epigenetic therapeutic inhibitors to elevate the levels of UNG2-Lys78 acetylation, leading to sensitizing ROS-resistant cancer cells to DNA damaging therapeutic agents. I close this commentary by briefly summarizing some outstanding questions and postulations in the field in the context of the novel findings presented by Bao et al.

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“…In mammals, Prdx-3 only accounts for 1.6% of soluble mitochondrial protein, but it is responsible for the detoxification of 90% of H 2 O 2 [ 39 ]. Under oxidative stress conditions, PRDX3 is recruited to UNG1 binding to mtDNA and combines with UNG1 through a disulphide bond, protecting UNG1 from degradation and preventing oxidative damage to mitochondrial DNA to enhance the cell resistance to oxidative stress [ 40 ]. Studies have reported that the deletion of PRDX3 resulted in increased H 2 O 2 in the mitochondria [ 41 ], and the levels of mitochondrial ROS in THP-1 cells with the PRDX3 gene knocked out was significantly higher than in controls [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway

Jin

Yang

et al. 2018

J Exp Clin Cancer Res

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BackgroundThe increase in the levels of reactive oxygen species (ROS) in acute myeloid leukemia (AML) patients has been previously described; thus, it is important to regulate ROS levels in AML.MethodsFlow cytometry were used to assess the in vitro effect of compound kushen injection (CKI). Quantitative proteomics were used to analyse the mechanism. The AML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of CKI.ResultsWe found that intracellular ROS levels in AML cells were decreased, the antioxidant capacity were increased when treated with CKI. CKI inhibited the proliferation of AML cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI promoted apoptosis and arrested cell cycle at G1/G0 phase in U937 cells. Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were identified in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI-treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the proteins Prdx2 could be Interacted with Trx1 by CKI treatment. In vivo, the survival was longer and the disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood in the CKI-treated group in the AML PDX model.ConclusionsAntioxidant CKI possess better clinical application against AML through the Prdxs/ROS/Trx1 signalling pathway.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0948-3) contains supplementary material, which is available to authorized users.

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Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

Cited by 22 publications

References 54 publications

The anterior gradient-2 interactome

The anterior gradient-2 interactome

A new insight into base excision repair (BER) in targeted cancer therapy

Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway

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