Regulatory role of phosphorylation of tumor suppressor Fhit protein

脆弱的FHIT基因是肿瘤前病变中DNA损伤的首要目标之一，最近的研究表明，FHIT蛋白参与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通过调控Fhit蛋白Y114的磷酸化来调节检查点反应。这种反应是由Atr激酶调节的，并确定了正常细胞和癌细胞的反应性。此外，在野生型造血细胞中观察到，暴露于基因毒素对苯二酚的fhit缺陷造血细胞对干细胞体外集落形成的抑制具有抗性。目前的研究结果表明，氧化应激的降低，加上有效但容易出错的DNA损伤修复，使得携带有害突变的基因毒素暴露的fhit缺陷造血干细胞能够在计划外的长期存活，这表明它在多步骤癌变中具有重要意义。

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.