Oncogene: The Chango team reveals new targets for tumor therapy targeting DNA replication pressure.

DNA as a living genetic material is aggregated from DNA polymerase, using DNA nucleonucleophosphate (dNTPs) as raw materials.
the reduction of nucleotide reductase (RIbonucleotide Reductase, RNR) to catalysis nucleoside diphosphate (NDP) to deoxynucleonucleophosphate (dNDP), which is the most important speed-limiting step in dNTPs from head synthesis.
RNR is an isogenic quadruped consisting of The Great eras RRM1 and the small sub-kilo RRM2.
in order to ensure the accuracy of DNA in the replication process and the stability of the genome, dNTPs raw material supply must be subject to strict fine space-time regulation.
it is well known that DNA replication is regulated by the cell cycle and occurs in Phase S.
in order to ensure the sufficient synthesis of dNTPs in The S phase, the level of the small sub-kiloRRM2 protein was significantly higher in The S/G2 phase than in the G1 phase.
however, the greater sub-rrM1 remains the same at different stages of the cell cycle.
in addition to raising the level of the RRM2 protein, there is still a lack of understanding of how to activate RNR in s-specific other molecular mechanisms.
recently, the Chenguo team of the University of Jinan published a research paper entitled "Cell cycle-replication phosphoryation of RRM1 ensures sei-dna and re-regulates-environment-vulnerability to ATR inhibition" in the form of Article Ins.
the paper (e.g. diagram) found that although rrM1 protein levels did not change significantly in the cell cycle process, RRM1 was phosphorylation disrfields edited by CDK2/CyclinA in S/G2 and its phosphorylation site was identified as Ser559.
structural analysis found that Ser559 is close to the RNR catalytic center, and biochemical experiments have proved that RRM1 Ser559 phosphorylation can enhance RNR enzyme activity.
phosphorylation inactivated mutant S559A can reduce intracellular dNTPs levels, induce DNA replication pressure and chromosomal abnormalities.
also, cells carrying RRM1 S559A can activate DNA damage stress kinase ATR.
inhibits ATR to induce the death of cells by producing lethal DNA replication pressure strain on cells expressing RRM1 S559A.
therefore, S/G2-specific activation of RNR is realized through RRM1 phosphorylation, which ensures sufficient supply of dNTPs raw materials in the DNA replication process, and provides a new molecular mechanism for DNA replication fidelity and genomic stability.
when CDK2/CyclinA-mediated RRM1 phosphorylation disorders, it induces obvious DNA replication pressure and DNA damage, and increases the antitumor efficiency of ATR inhibitors.
the work is supported by the Guangdong Natural Science Foundation, the Guangzhou Science and Technology Program, the Central University Research Fund and the National Natural Science Foundation. Dr.
Chen Guo is an independent correspondent for the work.
Author Profile: Chen Guo, a Ph.D. from Nanjing University in 2012, a postdoctoral training session at the University of Minnesota and Emory University from 2012 to 2018, and a professor and head of the research group at Emory University from 2018 to 2019, has been employed by Senior Scientist at Emory University since May 2019-to-present. Dr.
Chen Guo has long worked on the pharmacology of anti-tumor drugs that target DNA repair, and has authored or first-time authors to publish more than 30 papers in the journals J Clin Invest, Nature Communications, Cancer Research, Nucleic Acids Research, Oncogene (two) and Molecular Therapy, authoring a number of PCT international invention patents and Chinese patents.
served as editor or guest editor of academic journals such as Precise Oncology and Frontiers in Medicine, and received the Young Scientist Award from the Chinese Society for Biochemistry and Molecular Biology.
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