Regulatory role of phosphorylation of tumor suppressor Fhit protein

脆性FHIT基因是癌前病变中DNA损伤的首要靶点之一，最近的研究表明，FHIT蛋白参与了基因毒素暴露后基因组完整性和检查点反应的监测。我们研究了FHIT通过调节FHIT蛋白Y114位的磷酸化来调节检查点反应。这种反应是由ATR激酶调节的，并决定了正常细胞和癌细胞的反应性。此外，FHIT缺陷的造血细胞暴露在基因毒素氢醌中，对野生型造血细胞在体外观察到的干细胞克隆形成抑制具有抵抗力。目前的结果表明，氧化应激的减少，加上有效但容易出错的DNA损伤修复，允许携带有害突变的基因毒素暴露的FHIT缺陷造血干细胞意外、长期存活，这表明这在多步骤致癌中具有重要意义。

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.