title: Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation.
abstract: Isoform 1 of uracil-DNA glycosylase (UNG1) is the major protein for initiating base-excision repair in mitochondria and is in close proximity to the respiratory chain that generates reactive oxygen species (ROS). Effects of ROS on the stability of UNG1 have not been well characterized. In the present study, we found that overexpression of UNG1 enhanced cells' resistance to oxidative stress and protected mitochondrial DNA (mtDNA) from oxidation. Proteomics analysis showed that UNG1 bound to eight proteins in the mitochondria, including PAPSS2, CD70 antigen, and AGR2 under normal growth conditions, whereas UNG1 mainly bound to Peroxiredoxin 3 (PRDX3) via a disulfide linkage under oxidative stress. We further demonstrated that the UNG1-PRDX3 interaction protected UNG1 from ROS-mediated degradation and prevented mtDNA oxidation. Moreover, our results show that ROS-mediated UNG1 degradation was Lon protease 1 (LonP1)-dependent and mitochondrial UNG1 degradation was aggravated by knockdown of PRDX3 expression. Taken together, these results reveal a novel function of UNG1 in the recruitment of PRDX3 to mtDNA under oxidative stress, enabling protection of UNG1 and UNG1-bound DNA from ROS damage and enhancing cell resistance to oxidative stress.
authors.affiliation: MOE Key Laboratory of Bioinformatics and the Center of Biomedical Analsis, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Zhilei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Bioinformatics and the Center of Biomedical Analsis, School of Life Sciences, Tsinghua University, Beijing, China; Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: MOE Key Laboratory of Bioinformatics and the Center of Biomedical Analsis, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Gong
authors.affiliation: MOE Key Laboratory of Bioinformatics and the Center of Biomedical Analsis, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China.
authors.forename: Chongdong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China.
authors.forename: Qingtao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Bioinformatics and the Center of Biomedical Analsis, School of Life Sciences, Tsinghua University, Beijing, China. Electronic address: dht@mail.tsinghua.edu.cn.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
mesh_terms: D000072283:A549 Cells; D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism; D053282:CD27 Ligand / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009088:Mucoproteins; D015513:Oncogene Proteins; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D061105:Peroxiredoxin III / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051981:Uracil-DNA Glycosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: C502296:AGR2 protein, human; D053282:CD27 Ligand; C505771:CD70 protein, human; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D051981:Uracil-DNA Glycosidase; D049069:ATP-Dependent Proteases; C000595973:LONP1 protein, human
keywords: Degradation; Oxidative stress; Proteomics; UNG1; UNG1-PRDX3 interactions