Development of bio-dosimetry for the evaluation of low dose radiation and carcinogenic risk estimation

开发用于低剂量辐射评估和致癌风险评估的生物剂量测定法

• 批准号: 14380252
• 负责人: KAMIYA Kenji
• 金额: $ 9.02万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14380252/
• 关键词: Rev1; genome damage; DNA repair; translesion DNA synthesis; Double strand break; Radiation; Histone H2AX; Bio-dosimetry; ゲノム修復; 損傷乗り越えDNA複製; モニターマウス; 遺伝子損傷; 損傷乗越え修復; 2重鎖切断

We have tried to develop the hypersensitive mouse model and molecular bio-dosimery using DNA damage response proteins for the estimation of carcinogenic risk and dose after radiation exposure.1.Development of hypersensitive mouse model for radiation exposureRev1 protein belongs to a family of translesion DNA polymerases. Rev1 is responsible for error-prone translesion synthesis and play a role in mutagenesis induced by DNA damage. REV1 is deoxycytidyltransferase that incorporates dCMP opposite template abasic sites.In order to develop hypersensitive mouse model for radiation exposure, We have developed transgenic mouse (Tg) over expressing Rev1 gene under the constitutive zinc-induced transcriptional activation promoter. We've succeeded in establishing 7 Tg mouse line expressing Rev1 transgene. We examined sensitivity and mutation frequency of T-cell receptor (TCR) after radiation exposure, and found that Tg mouse was apt to have higher mutation frequency of TCR than normal mouse.2.Development of molecular bio-dosimery for low dose radiationIn order to develop molecular bio-dosimery, We have focused our research on functional analysis of Histone H2AX complex which is phosphorylated after induction of DNA damage (γ-H2AX) and visualized as foci in cell nucleus. We found that H2AX became highly mobile after induction of DSBs. We further find that mobilization depends not on phosphorylation but rather on ubiquitination, and that ubiquitination of H2AX is, in turn, regulated by TIP60 histone acetylase which implicates TIP60 in DNA repair. These results suggest that mobilization of H2AX is an early and necessary step in repair of DNA DSB.

我们尝试开发超敏小鼠模型和利用DNA损伤反应蛋白的分子生物剂量学来估计辐射暴露后的致癌风险和剂量。1.辐射暴露超敏小鼠模型的开发Rev1蛋白属于跨损伤DNA聚合酶家族Rev1 负责容易出错的跨损伤合成，并在 DNA 损伤诱导的诱变中发挥作用。为了开发辐射暴露过敏小鼠模型，我们开发了在组成型锌诱导转录激活启动子下过表达Rev1基因的转基因小鼠（Tg）。我们已经成功建立了7个表达Rev1转基因的Tg小鼠系。等检测了辐射照射后T细胞受体（TCR）的敏感性和突变频率，发现Tg小鼠比正常小鼠容易出现更高的TCR突变频率。2.低剂量辐射分子生物剂量学的发展为了开发分子生物剂量学，我们将研究重点放在组蛋白 H2AX 复合物的功能分析上，该复合物在诱导 DNA 损伤 (γ-H2AX) 后被磷酸化，并在细胞核中可视化为焦点，我们发现 H2AX 在诱导 DNA 损伤后变得高度移动。我们进一步发现，动员不依赖于磷酸化，而是依赖于泛素化，而 H2AX 的泛素化反过来又受到 TIP60 组蛋白的调节。这些结果表明，H2AX 的动员是 DNA DSB 修复的早期且必要的步骤。

项目成果

Functional analysis of new gene, cis-retinol/androgen dehydrogenase type3 (CRAD3), which was over-expressed in radiation-induced mouse hepatomas.

新基因顺式视黄醇/雄激素脱氢酶 3 型 (CRAD3) 的功能分析，该基因在辐射诱导的小鼠肝癌中过度表达。

• 发表时间: 2003
• 期刊: Clinical endocrinology 51 Supple
• 作者: Sumii;M.
• 通讯作者: M.

Ikura, T.: "Chromatin dynamics and DNA repair"Front. Biosci.. 8. 149-155 (2003)

Ikura, T.：“染色质动力学和 DNA 修复”前面。

Effects of radioactive iodine (^<131>I) on the thyroid of newborn, pubertal and adult rats.

放射性碘(^131I)对新生、青春期和成年大鼠甲状腺的影响。

• 发表时间: 2002
• 期刊: Proceedings of International Symposium on Radiation and Homeostasis(Ed.by Sugahara, T.)(Elsevier, Amsterdam, Netherland)
• 作者: Nitta;Y.
• 通讯作者: Y.

突然変異誘発に関与するヒトREV1タンパク質の機能ドメインの解析

人REV1蛋白参与诱变的功能域分析

• 发表时间: 2002
• 期刊: 広島医学 55・3
• 作者: 増田雄司

Masuda, Y.: "Structure and enzymatic properties of a stable complex of the human REV1 and REV7 proteins"J.Biol.Chem.. 278・14. 12356-12360 (2003)

Masuda, Y.：“人 REV1 和 REV7 蛋白的稳定复合物的结构和酶特性”J.Biol.Chem.. 278・14 (2003)。