title: Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways.
abstract: Radiotherapy causes the regression of many human tumors by increasing DNA damage, and the novel molecular mechanisms underlying the genomic instability leading to cancer progression and metastasis must be elucidated. Atypical dual-specificity phosphatase 3 (DUSP3) has been shown to down-regulate mitogen-activated protein kinases (MAPKs) to control the proliferation and apoptosis of human cancer cells. We have recently identified novel molecular targets of DUSP3 that function in DNA damage response and repair; however, whether DUSP3 affects these processes remains unknown.
  
  
  
  Tumor cell lines in which DUSP3 activity was suppressed by pharmacological inhibitors or a targeted siRNA were exposed to gamma radiation, and proliferation, survival, DNA strand breaks and recombination repair pathways were sequentially analyzed.
  
  
  
  The combination of reduced DUSP3 activity and gamma irradiation resulted in decreased cellular proliferation and survival and increased cellular senescence compared with the effects of radiation exposure alone. Gamma radiation-induced DNA damage was increased by the loss of DUSP3 activity and correlated with increased levels of phospho-H2AX protein and numbers of ionizing radiation-induced γ-H2AX foci, which were reflected in diminished efficiencies of homologous recombination (HR) and non-homologous end-joining (NHEJ) repair. Similar results were obtained in ATM-deficient cells, in which reduced DUSP3 activity increased radiosensitivity, independent of increased MAPK phosphorylation.
  
  
  
  The loss of DUSP3 activity markedly increases gamma radiation-induced DNA strand breaks, suggesting a potential novel role for DUSP3 in DNA repair.
  
  
  
  The radioresistance of tumor cells is effectively reduced by a combination of approaches through the inhibition of DUSPs.
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748, CEP:05508-900, Sao Paulo, SP, Brazil.
authors.forename: Thompson E P
authors.initials: TEP
authors.lastname: Torres
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748, CEP:05508-900, Sao Paulo, SP, Brazil.
authors.forename: Lilian C
authors.initials: LC
authors.lastname: Russo
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748, CEP:05508-900, Sao Paulo, SP, Brazil.
authors.forename: Alexsandro
authors.initials: A
authors.lastname: Santos
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748, CEP:05508-900, Sao Paulo, SP, Brazil.
authors.forename: Gabriela R
authors.initials: GR
authors.lastname: Marques
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748, CEP:05508-900, Sao Paulo, SP, Brazil.
authors.forename: Yuli T
authors.initials: YT
authors.lastname: Magalhaes
authors.affiliation: Department of Chemistry, Aligarh Muslim University, Aligarh 202002, UP, India.
authors.forename: Sartaj
authors.initials: S
authors.lastname: Tabassum
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes, 748, CEP:05508-900, Sao Paulo, SP, Brazil. Electronic address: flforti@iq.usp.br.
authors.forename: Fabio L
authors.initials: FL
authors.lastname: Forti
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D054640:Dual Specificity Phosphatase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D005720:Gamma Rays; D006657:Histones / Q000032:analysis; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000532:radiotherapy*; D011836:Radiation Tolerance
chemical_list: C468783:H2AX protein, human; D006657:Histones; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D020928:Mitogen-Activated Protein Kinases; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3
keywords: DNA damage response; DUSP3/VHR; Dual-specificity tyrosine phosphatases; Gamma radiation; HeLa and MeWo tumor cells; Recombination DNA repair mechanisms