4.7 Article

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

期刊

MOLECULAR ONCOLOGY
卷 16, 期 4, 页码 860-884

出版社

WILEY
DOI: 10.1002/1878-0261.13027

关键词

cancer; Fanconi anemia pathway; SIK2; spindle assembly checkpoint; synthetic lethality

类别

资金

  1. NHLBI/NIH [R56 HL132921-01, R01 HL132921-03]
  2. Heroes Foundation (IU Simon Cancer Center)
  3. Jeff Gordon' Children's Foundation (Riley Children's Foundation)
  4. St. Baldrick's foundation
  5. NCI Ruth L. Kirschstein National Research Service F30 Individual Fellowship Award [1F30CA200227]
  6. NIH Predoctoral Fellowship Award [T32 HL007910]
  7. Indiana Clinical and Translational Sciences Institute (CTSI) [UL1TR001108]
  8. IU Simon Cancer Center
  9. Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12-HD000850]
  10. NIH [T32 HL007910, T32 HD069047-06]
  11. NIH Diversity Supplement [3R01HL132921-03S1]

向作者/读者索取更多资源

The study reveals the dependence of FANCA-deficient cells on SIK2 for survival, suggesting a potential for targeting SIK2 in FA-disrupted cancers.
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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