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SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition.
Ma, Jian; Shi, Qing; Cui, Gaofeng; Sheng, Haoyue; Botuyan, Maria Victoria; Zhou, Yingke; Yan, Yuqian; He, Yundong; Wang, Liguo; Wang, Yuzhuo; Mer, Georges; Ye, Dingwei; Wang, Chenji; Huang, Haojie.
Afiliación
  • Ma J; Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • Shi Q; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • Cui G; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Sheng H; State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, 200438, China.
  • Botuyan MV; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Zhou Y; Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • Yan Y; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • He Y; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Wang L; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Wang Y; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Mer G; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Ye D; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Wang C; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
  • Huang H; Divison of Computational Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
Nat Commun ; 12(1): 5779, 2021 10 01.
Article en En | MEDLINE | ID: mdl-34599168
Geminin and its binding partner Cdt1 are essential for the regulation of DNA replication. Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. SPOP is frequently mutated in certain human cancer types and implicated in tumorigenesis. We show that cancer-associated SPOP mutations impair Geminin K27-linked poly-ubiquitination and induce replication origin over-firing and re-replication. The replication stress caused by SPOP mutations triggers replication catastrophe and cell death upon ATR inhibition. Our results reveal a tumor suppressor role of SPOP in preventing DNA replication over-firing and genome instability and suggest that SPOP-mutated tumors may be susceptible to ATR inhibitor therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Proteínas Nucleares / Complejos de Ubiquitina-Proteína Ligasa / Geminina Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Proteínas Nucleares / Complejos de Ubiquitina-Proteína Ligasa / Geminina Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido