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Studies on expression of radiation damage and modifying repair mechanisms

辐射损伤表达及修复机制研究

基本信息

批准号：
04304056
负责人：
SATO Kouki
金额：
$ 9.6万
依托单位：
National Institute of Radiological Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Co-operative Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04304056/
关键词：
DNA strand break photolyase excision repair UV skin cancer germ cell mutation X chromosome inactivation threshold-like response restriction length polymorphism しきい線量クローナリティ DNA二本鎖切断修復除去修復遺伝子紫外線損傷ユビキチン活性化酵素閾値様反応胸腺腫

项目摘要

We have demonstrated that the two mammalian cell mutants are hyper-sensitive to ionizing radiation and deficient in the repair of DNA double-strand breaks and that one of the repair genes is located on human chromosome 5. The photolyase genes from blue-green algae, insects, fish and rat kangaroo have been cloned and their base sequences have been determined. The human gene ERCC5 which normalizes the defect in an excision repair-deficient mutant has been cloned and sequenced, which is identical to the gene of human xeroderma pigmentosum group G.A skin carcinogenesis system has been established using experimental animals and the use of damage-specific monoclonal antibodies has revealed that the solar light-induced lesions in the skin increase with dose and disappear within 24 hours. A murine temperature-sensitive mutant of ubiquitin-activating enzyme is arrested at the G2 phase at restrictive temperature and undergoes pulverization of the chromosomes. Spontaneous germ cell mutation frequency in medaka (Oryzias latipes) is similar to that in mouse and dadiation-induced mutation frequency differs substantially according to the stages of differentiation and mutation. Mouse embryos that have the sex chromosome composition of XXY develop normally when an excess X is paternal but develop aberrantly when an excess X is maternal. The reason for this phenomenon is that maternal X chromosomes are inactivated. Repeated beta-ray irradiation (3 times a week) of mouse skin causes cancer in all animals but the one-time dose of 0.5 Gy causes no cancer during their lifetime. Hence the radiation carcinogenesis of mouse skin shows a threshold-like response. Most of the radiation-induced thymiclymphoma are derived from single cells and they are accompanied by clone-specific chromosomal aberrations. Female patients with hematopoietic diseases have been diagnosed using restriction fragment length polymorphism.

我们已经证明，这两个哺乳动物细胞突变体是超敏感的电离辐射和DNA双链断裂的修复缺陷，修复基因之一位于人类5号染色体上。已克隆了蓝藻、昆虫、鱼类和袋鼠的光裂合酶基因，并测定了其碱基序列。已克隆和测序了使切除修复缺陷突变体中的缺陷正常化的人类基因ERCC 5，其与人类着色性干皮病G组的基因相同。已使用实验动物建立了皮肤致癌系统，并且使用损伤特异性单克隆抗体揭示了太阳光诱导的皮肤损伤随剂量增加而增加，并在24小时内消失。一种小鼠温度敏感的突变体的泛素激活酶被逮捕在G2期在限制性温度和染色体粉碎。青鳉（Oryzias latipes）生殖细胞的自发突变频率与小鼠相似，辐射诱发的突变频率则因分化和突变阶段的不同而有很大差异。具有XXY性染色体组成的小鼠胚胎在父源性X过多时发育正常，但在母源性X过多时发育异常。这种现象的原因是母亲的X染色体失活。小鼠皮肤的重复β射线照射（每周3次）在所有动物中引起癌症，但0.5戈伊的一次性剂量在其一生中不会引起癌症。因此，小鼠皮肤的辐射致癌作用表现出阈值样反应。大多数辐射诱发的胸腺淋巴瘤起源于单细胞，并伴有克隆特异性染色体畸变。已使用限制性片段长度多态性诊断患有造血系统疾病的女性患者。