title: ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG.
abstract: BACKGROUND
  N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent and an environmental carcinogen, causes DNA lesions and even carcinomas. DNA damage responses induced by MNNG activate various DNA repair genes and related signaling pathways. The present study aimed to investigate the regulatory mechanisms of human RR small subunit M2 (hRRM2) in response to MNNG.
  
  
  RESULTS
  In this study, we demonstrated that the RRM2 gene was transactivated by MNNG exposure more strongly than the other small subunit, p53R2. The upregulated RRM2 translocated to the nucleus for DNA repair. Further study showed that E2F3 transactivated RRM2 expression by directly binding to its promoter after MNNG exposure. The transactivation was enhanced by the upregulation of NFY, which bound to the RRM2 promoter adjacent to the E2F3 binding site and interacted with E2F3. In response to MNNG treatment, E2F3 accumulated mainly through its phosphorylation at S124 and was dependent on ATR-CHK1 signaling. In comparison, p53R2 played a relatively weaker role in the MNNG-induced DNA damage response, and its transcription was regulated by the ATR-CHK2-E2F1/p53 pathway.
  
  
  CONCLUSIONS
  We suggest that MNNG-stimulated ATR/CHK1 signaling stabilizes E2F3 by S124 phosphorylation, and then E2F3 together with NFY co-transactivate RRM2 expression for DNA repair.
  
  
  CONCLUSIONS
  We propose a new mechanism for RRM2 regulation to maintain genome stability in response to environmental chemical carcinogens.
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Chaoju
authors.initials: C
authors.lastname: Gong
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Normal University, Jinhua People's Hospital Joint Center for Biomedical Research, Jinhua 321004, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhong
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Lou
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Tingyang
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: shaojimin@zju.edu.cn.
authors.forename: Jimin
authors.initials: J
authors.lastname: Shao
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000096:biosynthesis; D002273:Carcinogens / Q000633:toxicity; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000187:drug effects; D042822:Genomic Instability; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012262:Ribonucleoside Diphosphate Reductase / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D023081:CCAAT-Binding Factor; D002273:Carcinogens; D004268:DNA-Binding Proteins; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D016159:Tumor Suppressor Protein p53; C402244:nuclear factor Y; D008769:Methylnitronitrosoguanidine; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: DNA repair; E2F3; Human ribonucleotide reductase small subunit M2 (RRM2); MNNG; Transcriptional regulation