Regulatory role of phosphorylation of tumor suppressor Fhit protein

脆性FHIT基因是肿瘤前病变中DNA损伤的第一靶标之一，最近的研究表明，Fhit蛋白参与基因组完整性和基因毒素暴露后检查点反应的监测。我们研究了Fhit通过调控Fhit蛋白Y114位点的磷酸化来调节检查点反应。该反应受Atr激酶调节，并定义了正常和癌细胞的反应性。此外，暴露于遗传毒素氢醌的Fhit缺陷型造血细胞对用野生型造血细胞观察到的干细胞体外集落形成的抑制具有抗性。目前的结果表明，减少氧化应激，加上有效的，但容易出错的DNA损伤修复，允许计划外的，长期生存的基因毒素暴露的Fhit缺陷的造血干细胞携带有害的突变，这表明在多步骤致癌的意义。

The fragile FHIT gene is among the first targets of DNA damage in preneoplastic lesions and recent studies have shown that Fhit protein is involved in surveillance of genome integrity and checkpoint response after genotoxin exposure. We studied that Fhit modulate the checkpoint response via regulation of phosphorylation at Y114 of Fhit protein. The response was regulated Atr kinase, and define the responsiveness of normal and cancer cells. Furthermore, Fhit-deficient hematopoietic cells, exposed to the genotoxin hydroquinone, are resistant to the suppression of stem cell in vitro colony formation observed with wild type hematopoietic cells. The present results indicate that reduced oxidative stress, coupled with efficient but error-prone DNA damage repair, allows unscheduled, long-term survival of genotoxin-exposed Fhit-deficient hematopoietic stem cells carrying deleterious mutations, suggesting the significance in the multistep carcinogenesis.