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SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA-deficient cells.
Chan, Ka-Kui; Abdul-Sater, Zahi; Sheth, Aditya; Mitchell, Dana K; Sharma, Richa; Edwards, Donna M; He, Ying; Nalepa, Grzegorz; Rhodes, Steven D; Clapp, D Wade; Sierra Potchanant, Elizabeth A.
Afiliación
  • Chan KK; Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Abdul-Sater Z; Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Sheth A; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Mitchell DK; Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Sharma R; Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Edwards DM; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • He Y; Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Nalepa G; Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Rhodes SD; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Clapp DW; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Sierra Potchanant EA; Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
Mol Oncol ; 16(4): 860-884, 2022 02.
Article en En | MEDLINE | ID: mdl-34058059
The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here, we performed a kinome-wide synthetic lethality screen in FANCA-/- fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA. We found that FANCA colocalizes with SIK2 at multiple mitotic structures and regulates the activity of SIK2 at centrosomes. Furthermore, we found that loss of FANCA exacerbates cell cycle defects induced by pharmacological inhibition of SIK2, including impaired G2-M transition, delayed mitotic progression, and cytokinesis failure. In addition, we showed that inhibition of SIK2 abrogates nocodazole-induced prometaphase arrest, suggesting a novel role for SIK2 in the spindle assembly checkpoint. Together, these findings demonstrate that FANCA-deficient cells are dependent upon SIK2 for survival, supporting a preclinical rationale for targeting of SIK2 in FA-disrupted cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anemia de Fanconi Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Oncol Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anemia de Fanconi Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Oncol Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos