Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential.
Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential.
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DOI：
10.1042/bcj20220101
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发表时间：
2022-10-14
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Claspin是DNA复制应激后S期CHK 1的ATR依赖性磷酸化所需的衔接蛋白。Claspin表达在癌症中高度可变，低水平通常与患者生存率差相关。为了更多地了解Claspin表达减少的生物学后果及其对肿瘤发生的影响，我们研究了Clspn基因杂合敲除的小鼠。Claspin单倍不足导致女性生育力降低和卵母细胞减数分裂I细胞周期进展的母系遗传缺陷。此外，老年Clspn+/−小鼠出现自发性淋巴样增生，并增加了对非酒精性脂肪肝疾病的易感性。重要的是，我们证明了Claspin的肿瘤抑制作用。在肝细胞癌的DEN模型中，Claspin水平降低导致肝损伤和肿瘤发生增加。这些数据表明，Clspn单倍不足具有广泛的意想不到的生物学效应，并确立了Claspin作为控制肿瘤发生和多种疾病病因的调控节点的重要性。
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.