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Lookup NU author(s): Dr Suzanne Madgwick, Dr Saimir LuliORCiD, Helene Sellier, Dr Jacqueline Butterworth, Dr Jack LeslieORCiD, Adam Moore, Emma Corbin, Dr Adrian Yemm, Robson Chiremba, Dr Dina Tiniakos, Professor Fiona OakleyORCiD, Professor Neil PerkinsORCiD, Dr Jill Hunter
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The Author(s).Claspin is an adaptor protein required for ATR-dependent phosphorylation of CHK1 during S-phase following DNA replication stress. Claspin expression is highly variable in cancer, with low levels frequently correlating with poor patient survival. To learn more about the biological consequences of reduced Claspin expression and its effects on tumorigenesis, we investigated mice with a heterozygous knockout of the Clspn gene. Claspin haploinsufficiency resulted in reduced female fertility and a maternally inherited defect in oocyte meiosis I cell cycle progression. Furthermore, aged Clspn+/- mice developed spontaneous lymphoid hyperplasia and increased susceptibility to non-alcoholic fatty liver disease. Importantly, we demonstrate a tumour suppressor role for Claspin. Reduced Claspin levels result in increased liver damage and tumourigenesis in the DEN model of hepatocellular carcinoma. These data reveal that Clspn haploinsufficiency has widespread unanticipated biological effects and establishes the importance of Claspin as a regulatory node controlling tumorigenesis and multiple disease aetiologies.
Author(s): Madgwick S, Luli S, Sellier H, Butterworth JA, Leslie J, Moore AJ, Corbin EK, Yemm AI, Chiremba RT, Tiniakos D, Oakley F, Perkins ND, Hunter JE
Publication type: Article
Publication status: Published
Journal: Biochemical Journal
Year: 2022
Volume: 479
Issue: 19
Pages: 2115-2130
Print publication date: 01/10/2022
Online publication date: 23/09/2022
Acceptance date: 23/09/2022
Date deposited: 02/11/2022
ISSN (print): 0264-6021
ISSN (electronic): 1470-8728
Publisher: Portland Press
URL: https://doi.org/10.1042/BCJ20220101
DOI: 10.1042/BCJ20220101
PubMed id: 36240068
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