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Overactivated Cdc42 acts through Cdc42EP3/Borg2 and NCK to trigger DNA damage response signaling and sensitize cells to DNA-damaging agents.
Eduardo da Silva, Luiz; Russo, Lilian Cristina; Forti, Fabio Luis.
Afiliação
  • Eduardo da Silva L; Laboratory of Biomolecular Systems Signaling, Department of Biochemistry, Institute of Chemistry, University of São Paulo, SP, Brazil.
  • Russo LC; Laboratory of Biomolecular Systems Signaling, Department of Biochemistry, Institute of Chemistry, University of São Paulo, SP, Brazil.
  • Forti FL; Laboratory of Biomolecular Systems Signaling, Department of Biochemistry, Institute of Chemistry, University of São Paulo, SP, Brazil. Electronic address: flforti@iq.usp.br.
Exp Cell Res ; 395(2): 112206, 2020 10 15.
Article em En | MEDLINE | ID: mdl-32739212
The small GTPase Cdc42, a member of the Rho family, regulates essential biological processes such as cytoskeleton remodeling, migration, vesicular trafficking and cell cycle. It was demonstrated that Cdc42 overactivation through different molecular strategies increases cell sensitivity to genotoxic stress and affects the phosphorylation status of DNA damage response proteins by unknown mechanisms. By using a combination of approaches including affinity purification/mass spectrometry (AP/MS) and colocalization microscopy analysis we were able to identify Cdc42EP3/Borg2 as a putative molecular effector of these molecular and cellular events that seem to be independent of cell line or DNA damage stimuli. We then investigated the influence of Cdc42EP3/Borg2 and other potential protein partners, such as the NCK and Septin2 proteins, which could mediate cellular responses to genotoxic stress under different backgrounds of Cdc42 activity. Clonogenic assays showed a reduced cell survival when ectopically expressing the Cdc42EP3/Borg2, NCK2 or Septin2 in an overactivated Cdc42-dependent background. Moreover, endogenous NCK appears to relocate into the nucleus upon Cdc42 overactivation, especially under genotoxic stress, and promotes the suppression of Chk1 phosphorylation. In sum, our findings reinforce Cdc42 as an important player involved in the DNA damage response acting through Cdc42EP3/Borg2 and NCK proteins following genomic instability conditions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Proteínas Oncogênicas / Proteína cdc42 de Ligação ao GTP / Reguladores de Proteínas de Ligação ao GTP / Proteínas Adaptadoras de Transdução de Sinal Tipo de estudo: Prognostic_studies Idioma: En Revista: Exp Cell Res Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Proteínas Oncogênicas / Proteína cdc42 de Ligação ao GTP / Reguladores de Proteínas de Ligação ao GTP / Proteínas Adaptadoras de Transdução de Sinal Tipo de estudo: Prognostic_studies Idioma: En Revista: Exp Cell Res Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos