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中国生物化学与分子生物学会2019年全国学术会议暨学会...

作者： Guo Chen Jun Fan Youwei Sun Michael Lammers Xingming Deng Department of Medical Biochemistry and Molecular Biology School of Medicine Jinan University Departments of Radiation Oncology Emory University School of Medicine and Winship Cancer Institute of Emory University Institute of Biochemistry Synthetic and Structural Biochemistry University of Greifswald

ribonucleotide reductase(RNR), composed of RRM1 and RRM2 subunits, catalyzes the rate-limiting step in the de novo synthesis of deoxyribonucleotides triphosphate(dNTP) needed for DNA synthesis. Although allosteric regulation has been defined to control its activity to manipulate the dNTP pool balance and genomic integrity, insight into fine regulation is still limited. Here, we report that acetylation and deacetylation of the RRM2 subunit of RNR acts as a molecular switch that impacts RNR activity, dNTP synthesis, and DNA replication fork progression. Acetylation of RRM2 at K95 abrogates RNR activity by disrupting its homodimer assembly. RRM2 is directly acetylated by KAT7, and deacetylated by Sirt2, respectively. Sirt2, which level peak in S phase, sustains RNR activity at or above a threshold level required for dNTPs synthesis. We also find that radiation or camptothecin-induced DNA damage promotes RRM2 deacetylation by enhancing Sirt2-RRM2 interaction. Acetylation of RRM2 at K95 results in the reduction of the dNTP pool, DNA replication fork stalling, and the suppression of tumor cell growth in vitro and in vivo. This study therefore identifies acetylation as a regulatory mechanism governing RNR activity.

关键词： ribonucleotide reductase Acetylation Cancer nucleotide metabolism

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p53R2,a novel p53-controlled ribonucleotide reductase subunit involved in DNA damage repair and its role in tumorigenesis and cancer treatment

p53R2,a novel p53-controlled ribonucleotide reductase subuni...

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2008年中国病理生理学会第十一届肿瘤和第十二届免疫专...

作者： Chen Xinhuan Yun Yen Jimin Shao Department of Pathology and Pathophysiology,Zhejiang University School of Medicine

＜正＞Human ribonucleotide reductase （hRR） catalyzes the reduction of ribonucleotides to their corresponding deoxyribonucleotides,which are the building blocks for DNA replication and repair. The enzyme is composed of two identical large （hRRM1） and two identical small （hRRM2） subunits,p53R2 is a newly identified p53-inducible protein which has～80%sequence homology with hRRM2.The p53R2 gene contains a p53-binding site in intron 1.The expression ofp53R2,but not hRRM2,is induced by ultraviolet light,r-irradiation or DNA-damaging agents in a p53-dependent manner.Furthermore,p53 can interact with p53R2 and hRRM2 at the protein level to regulate RR activity in response to genomic stress.Cells that fail to make p53R2 are more sensitive to killing by DNA-damaging agents.A study using p53R2 knockout mice showed that impairment of the p53R2-involved DNA repair pathway enhances the frequency of spontaneous mutations and activates p53-dependent apoptotic pathway（s）.These findings lead to the hypothesis that there are two pathways in human cells to supply dNTPs for DNA synthesis:one through the activity of hRRM2,involved in normal maintenance of dNTPs for DNA replication during the S phase in a cell cycle-dependent manner,and the other through p53R2,supplying dNTPs for DNA repair in G0/G1 cells in a p53-dependent manner.Recently,p53R2 has been shown to possess a crucial role in dNTP supply for mtDNA synthesis.The other functions of p53R2,such as facilitates p21 induction of G1 arrest under UV irradiation,are also proposed.The discovery of p53R2 has created much interest in its molecular characteristics and its possible role in tumorigenesis and cancer treatment.Some investigations have shown that alterations of p53R2 may have implication in tumor development and metastasis.The key role of hRR in DNA synthesis and cell growth control has made it an important target for anticancer therapy,p53R2,functioning in p53-dependent DNA repair pathway,may have the potential to be considered as a new therapeutic target for human cancer trea

关键词： p53R2 ribonucleotide reductase DNA damage repair tumorigenesis cancer treatment

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p53R2,a novel p53-controlled ribonucleotide reductase subunit involved in DNA damage repair and its role in tumorigenesis and cancer treatment

p53R2,a novel p53-controlled ribonucleotide reductase subuni...

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浙江省生理科学会2008年学术年会

作者：陈新焕江红娟邵吉民 Department of Pathology and Pathophysiology Zhejiang University School of Medicine

Human ribonucleotide reductase(hRR) catalyzes the reduction of ribonucleotides to their corresponding deoxyribonucleotides,which are the building blocks for DNA replication and repair.The enzyme is composed of two identical large(hRRM1) and two identical small(hRRM2) subunits.p53R2 is a newly identified p53-inducible protein which has～80%sequence homology

关键词： p53R2 ribonucleotide reductase DNA damage repair tumorigenesis cancer treatment

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RR1 and RR2 gene deletion affects the immunogenicity of a live attenuated pseudorabies virus vaccine candidate in natural pig host

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Frontiers of Agricultural Science and Engineering 2016年第1期3卷 81-86页

作者： Shijun YAN He YAN Chaolin ZHANG Tongyan WANG Qingyuan YANG Zhe SUN Yan XIAO Feifei TAN Xiangdong LI Kegong TIAN National Research Center for Veterinary Medicine College of Animal Science and Veterinary Medicine Henan Agricultural University

As virulence-determining genes, RR1 and RR2 encode the small subunit and large subunit of viral ribonucleotide reductase(RR) in pseudorabies virus which have been extensively studied in mice. However,their role in pigs has not been adequately investigated. In this study, we deleted RR1 and RR2 genes based on a TK/g E/g I triple gene-deleted pseudorabies virus and tested its efficacy in pigs as a vaccine candidate. The rescued virus showed similar growth properties and plaque size in vitro as its parent strain. In an animal study, the virus could elicit humoral immune responses shown by generation of g B-specific antibodies and virus neutralizing antibodies.However, vaccination could not provide protection against virulent pseudorabies virus challenge since vaccinated pigs showed clinical pseudorabies-specific syndromes. The deficiency in protection may due to the generation of late and low levels of gB antibodies and virus neutralizing antibodies.

关键词： pseudorabies virus RR1 and RR2 ribonucleotide reductase vaccine candidate

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