FANCD1 plays predominant role in the repair of DNA damage induced by ACNU or TMZ.

FANCD1 在修复 ACNU 或 TMZ 诱导的 DNA 损伤中起主要作用。

• 批准号: 22890095
• 负责人: KONDO Natsuko
• 金额: $ 1.83万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22890095/
• 关键词: FANCD1; テモゾロミド(TMZ); 塩酸ニムスチン(ACNU); HomologousRecombination修復経路; グリオブラストーマ; Homologous Recombination修復経路; ファンコニ貧血; DNA修復路; 悪性グリオーマ

Nimustine(ACNU) and temozolomide(TMZ) are DNA alkylating agents which are commonly used in chemotherapy for glioblastomas. ACNU is a DNA cross-linking agent and TMZ is a methylating agent. The therapeutic efficacy of these agents is limited by the development of resistance. In this work, the role of the Fanconi anemia(FA) repair pathway for DNA damage induced by ACNU or TMZ was examined. Cultured mouse embryonic fibroblasts were used : FANCA^<-/->, FANCC^<-/->, FANCA^<-/-> C^<-/->, FANCD2^<-/-> cells and their parental cells, and Chinese hamster ovary and lung fibroblast cells were used : FANCD1/BRCA2mt, FANCG^<-/-> and their parental cells. Cell survival was examined after a 3 h ACNU or TMZ treatment by using colony formation assays. All FA repair pathways were involved in ACNU-induced DNA damage. However, FANCG and FANCD1/BRCA2 played notably important roles in the repair of TMZ-induced DNA damage. The most effective molecular target correlating with cellular sensitivity to both ACNU and TMZ was FANCD1/BRCA2. In addition, it was found that FANCD1/BRCA2 small interference RNA efficiently enhanced cellular sensitivity toward ACNU and TMZ in human glioblastoma A172 cells. These findings suggest that the down-regulation of FANCD1/BRCA2 might be an effective strategy to increase cellular chemo-sensitization towards ACNU and TMZ.

尼莫司汀(Nimustine，ACNU)和替莫唑胺(temozolomide，TMZ)是胶质母细胞瘤化疗中常用的DNA烷化剂。ACNU是DNA交联剂，TMZ是甲基化试剂。这些药物的治疗效果受到耐药性发展的限制。本工作研究了Fanconi贫血(FA)修复通路在ACNU或TMZ诱导的DNA损伤中的作用。使用培养的小鼠胚胎成纤维细胞：FANCA^&lt；-/-&gt；，FANCC^&lt；-/-&gt；-/-&gt；，FANCD2^&lt；-/-&gt；细胞及其亲代细胞，以及中国仓鼠卵巢和肺成纤维细胞：FANCD1/BRCA2mt，FANCG^&lt；-/-&gt；及其亲代细胞。用集落形成实验检测ACNU或TMZ作用3h后的细胞存活率。所有FA修复途径都参与了ACNU诱导的DNA损伤。然而，FANCG和FANCD1/BRCA2在TMZ诱导的DNA损伤修复中起着非常重要的作用。与细胞对ACNU和TMZ敏感性相关的最有效的分子靶点是FANCD1/BRCA2。此外，还发现FANCD1/BRCA2小干扰RNA有效地增强了人胶质母细胞瘤A172细胞对ACNU和TMZ的敏感性。这些结果提示，下调FANCD1/BRCA2可能是增加细胞对ACNU和TMZ化疗敏感性的有效策略。

项目成果

DNA damage induced by alkylating agents and repair pathways.

• DOI: 10.4061/2010/543531
• 发表时间: 2010-11-21
• 期刊: Journal of nucleic acids
• 影响因子: 2.3
• 作者: Kondo N;Takahashi A;Ono K;Ohnishi T
• 通讯作者: Ohnishi T

siRNA targeted for NBS1 enhances heat sensitivity in human anaplastic thyroid carcinoma cells

• DOI: 10.3109/02656736.2010.545365
• 发表时间: 2011-04
• 期刊: International Journal of Hyperthermia
• 影响因子: 3.1
• 作者: N. Okamoto;A. Takahashi;I. Ota;K. Ohnishi;Eiichiro Mori;N. Kondo;Taichi Noda;Y. Nakagawa;H. Uemura;Katunari Yane;H. Hosoi;T. Ohnishi

Repair pathways independent of the Fanconi anemia nuclear core complex play a predominant role in mitigating formaldehyde-induced DNA damage

• DOI: 10.1016/j.bbrc.2010.11.094
• 发表时间: 2011-01-07
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Noda, Taichi;Takahashi, Akihisa;Ohnishi, Takeo
• 通讯作者: Ohnishi, Takeo

Nitric Oxide Radical-induced Radioadaptation and Radiosensitization Are G2/M Phase-dependent

一氧化氮自由基诱导的放射适应和放射增敏是 G2/M 阶段依赖性的

• DOI: 10.1269/jrr.11026
• 发表时间: 2011
• 期刊: Journal of Radiation Research
• 影响因子: 2
• 作者: Su;X.
• 通讯作者: X.

FANCD1 and FANCG play predominant roles in the repair of DNA damage induced by ACNU or TMZ

FANCD1 和 FANCG 在 ACNU 或 TMZ 诱导的 DNA 损伤修复中起主要作用

• 发表时间: 2010
• 作者: Kondo N;Takahaehi A;Mori E;et al
• 通讯作者: et al