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

Authors :
Ka‐Kui Chan
Zahi Abdul‐Sater
Aditya Sheth
Dana K. Mitchell
Richa Sharma
Donna M. Edwards
Ying He
Grzegorz Nalepa
Steven D. Rhodes
D. Wade Clapp
Elizabeth A. Sierra Potchanant
Source :
Molecular Oncology, Vol 16, Iss 4, Pp 860-884 (2022)
Publication Year :
2022
Publisher :
Wiley, 2022.

Abstract

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.

Details

Language :
English
ISSN :
18780261 and 15747891
Volume :
16
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Molecular Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.f81c065551f42e1919675d6c2a442a5
Document Type :
article
Full Text :
https://doi.org/10.1002/1878-0261.13027