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

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 red...

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Autores principales: Madgwick, Suzanne, Luli, Saimir, Sellier, Helene, Butterworth, Jacqueline A., Leslie, Jack, Moore, Adam J., Corbin, Emma K., Yemm, Adrian I., Chiremba, Robson T., Tiniakos, Dina, Oakley, Fiona, Perkins, Neil D., Hunter, Jill E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704638/
https://www.ncbi.nlm.nih.gov/pubmed/36240068
http://dx.doi.org/10.1042/BCJ20220101
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author Madgwick, Suzanne
Luli, Saimir
Sellier, Helene
Butterworth, Jacqueline A.
Leslie, Jack
Moore, Adam J.
Corbin, Emma K.
Yemm, Adrian I.
Chiremba, Robson T.
Tiniakos, Dina
Oakley, Fiona
Perkins, Neil D.
Hunter, Jill E.
author_facet Madgwick, Suzanne
Luli, Saimir
Sellier, Helene
Butterworth, Jacqueline A.
Leslie, Jack
Moore, Adam J.
Corbin, Emma K.
Yemm, Adrian I.
Chiremba, Robson T.
Tiniakos, Dina
Oakley, Fiona
Perkins, Neil D.
Hunter, Jill E.
author_sort Madgwick, Suzanne
collection PubMed
description 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.
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spelling pubmed-97046382022-12-06 Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential Madgwick, Suzanne Luli, Saimir Sellier, Helene Butterworth, Jacqueline A. Leslie, Jack Moore, Adam J. Corbin, Emma K. Yemm, Adrian I. Chiremba, Robson T. Tiniakos, Dina Oakley, Fiona Perkins, Neil D. Hunter, Jill E. Biochem J Cancer 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. Portland Press Ltd. 2022-10-14 /pmc/articles/PMC9704638/ /pubmed/36240068 http://dx.doi.org/10.1042/BCJ20220101 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . Open access for this article was enabled by the participation of University of Liverpool in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with JISC.
spellingShingle Cancer
Madgwick, Suzanne
Luli, Saimir
Sellier, Helene
Butterworth, Jacqueline A.
Leslie, Jack
Moore, Adam J.
Corbin, Emma K.
Yemm, Adrian I.
Chiremba, Robson T.
Tiniakos, Dina
Oakley, Fiona
Perkins, Neil D.
Hunter, Jill E.
Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
title Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
title_full Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
title_fullStr Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
title_full_unstemmed Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
title_short Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
title_sort claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential
topic Cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704638/
https://www.ncbi.nlm.nih.gov/pubmed/36240068
http://dx.doi.org/10.1042/BCJ20220101
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