SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA‐deficient cells

Molecular Oncology

Donna M. Edwards¹  Aditya Sheth²  Ka‐Kui Chan³  Elizabeth A. Sierra Potchanant³  Grzegorz Nalepa³  D. Wade Clapp³  Ying He³  Zahi Abdul‐Sater³  Dana K. Mitchell³  Richa Sharma³  Steven D. Rhodes⁴ 

[1] Department of Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis IN USA;Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN USA;Department of Pediatrics Riley Hospital for Children Indiana University School of Medicine Indianapolis IN USA;Division of Pediatric Hematology‐Oncology Indiana University School of Medicine Indianapolis IN USA;

关键词: cancer;    Fanconi anemia pathway;    SIK2;    spindle assembly checkpoint;    synthetic lethality;   

DOI  :  10.1002/1878-0261.13027

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown