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

Ka-Kui Chan1, Zahi Abdul-Sater1, Aditya Sheth2

  • 1Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.

Molecular Oncology
|May 31, 2021
PubMed

Insights

Fanconi anemia (FA) pathway proteins are crucial for genomic stability. Loss of FANCA makes cells dependent on the mitotic kinase SIK2 for survival, suggesting SIK2 as a therapeutic target in FA-disrupted cancers.

Area of Science:

  • Genetics
  • Cell Biology
  • Cancer Biology

Background:

  • The Fanconi anemia (FA) pathway is essential for maintaining genomic stability, primarily through DNA damage repair during interphase.
  • While the tumor-suppressive role of FA proteins is recognized, their specific functions during mitosis remain less understood.

Purpose of the Study:

  • To investigate the role of FA proteins in mitosis and identify novel therapeutic targets in FA-disrupted cancers.
  • To explore the functional relationship between FANCA and mitotic kinases.

Main Methods:

  • A kinome-wide synthetic lethality screen was conducted in FANCA-deficient (FANCA-/-) fibroblasts.
  • Immunofluorescence microscopy was used to assess the colocalization and regulation of SIK2 by FANCA.
  • Pharmacological inhibition of SIK2 and nocodazole treatment were employed to evaluate cell cycle progression and spindle assembly checkpoint function.

Main Results:

  • SIK2 (Salt-Inducible Kinase 2) was identified as a synthetic lethal partner upon loss of FANCA.
  • FANCA colocalizes with SIK2 at mitotic structures and regulates its activity at centrosomes.
  • Loss of FANCA exacerbates cell cycle defects upon SIK2 inhibition, including impaired G2-M transition, delayed mitosis, and cytokinesis failure.
  • SIK2 inhibition abrogated nocodazole-induced prometaphase arrest, indicating a role in the spindle assembly checkpoint.

Conclusions:

  • FANCA-deficient cells exhibit a dependency on SIK2 for survival.
  • SIK2 plays a critical role in mitotic progression and the spindle assembly checkpoint in the context of FA deficiency.
  • Targeting SIK2 presents a potential therapeutic strategy for cancers with defects in the Fanconi anemia pathway.
Keywords:
Fanconi anemia pathwaySIK2cancerspindle assembly checkpointsynthetic lethality

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