Document Type
Article
Journal Title
Cancers
Publication Date
2026
Volume
18
Abstract
BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinomas (PDACs) are lethal tumors exhibiting resistance to most cancer therapeutics, particularly DNA-damaging agents. The
METHODS: Western blot analyses were used to assess the impacts of Rac1 inhibition on the components of the ATR/Chk1 cascade.
RESULTS: Here, we show that Rac1 inhibition disrupts ATR/Chk1 signaling by promoting degradation of Claspin, a key component of the fork protection complex needed for the Ser345-phosphorylation of Chk1 by ATR. In PDACs and normal pancreatic ductal cells, Rac1 inhibition (via inhibitors or siRNA) decreased Claspin protein levels without affecting its mRNA, reflecting a >3-fold reduction in Claspin's half-life. Claspin contains a phosphodegron recognized by SCF
CONCLUSIONS: These findings identify Rac1 as a critical regulator of ATR/Chk1 signaling through stabilization of the fork protection protein Claspin. Rac1 inhibition promotes the βTrCP-dependent, proteasome-mediated degradation of Claspin via its phosphodegron, thereby impairing Chk1 activation in response to DNA damage.
ISSN
2072-6694
DOI Link
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Chaudhary, Neha; Somers, Tabbatha N.; Batra, Surinder K.; Yan, Ying; and Ouellette, Michel M., "Rac1 GTPase Regulates the SCFβTrCP-Mediated Degradation of Claspin and the Cellular Response of Pancreatic Cancer Cells to Gamma Rays" (2026). Journal Articles: Biochemistry & Molecular Biology. 187.
https://digitalcommons.unmc.edu/com_bio_articles/187