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.

中文翻译：

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Claspin 单倍体不足导致生育能力缺陷、增生和致癌潜力增加

Claspin 是 DNA 复制应激后 S 期 ATR 依赖性 CHK1 磷酸化所需的衔接蛋白。Claspin 表达在癌症中变化很大，低水平通常与患者存活率低相关。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 单倍体不足导致女性生育能力降低和卵母细胞减数分裂 I 细胞周期进程中的母系遗传缺陷。此外，年老的 Clspn+/- 小鼠出现自发性淋巴组织增生并增加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 水平降低会导致肝损伤和肿瘤发生增加。这些数据表明 Clspn 单倍剂量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节节点的重要性。