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Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential

Lookup NU author(s): Dr Suzanne Madgwick, Dr Saimir Luli, 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

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
087961
062376
094409
11022Bloodwise (Formerly Leukaemia and Lymphoma Research)
BB/M018318/1Biotechnology and Biological Sciences Research Council (BBSRC)
C1443/A12750Cancer Research UK CRUK (open competition)
C1443/A22095Cancer Research UK CRUK (open competition)
MR/T010789/1
Wellcome Trust

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