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

尼莫司汀（ACNU）和替莫唑胺（TMZ）是DNA烷基化剂，常用于胶质母细胞瘤的化疗。ACNU是一种DNA交联剂，TMZ是一种甲基化剂。这些药物的治疗效果受到耐药性发展的限制。本研究探讨了Fanconi贫血（FA）修复途径在ACNU或TMZ诱导的DNA损伤中的作用。采用培养的小鼠胚胎成纤维细胞：FANCA^<-/->, FANCC^<-/->, FANCA^<-/-> C^<-/->, FANCD2^<-/->细胞及其亲本细胞，中国仓鼠卵巢和肺成纤维细胞：FANCD1/BRCA2mt， FANCG^<-/->及其亲本细胞。用菌落形成法检测ACNU或TMZ作用3 h后细胞存活情况。所有FA修复途径均参与acnu诱导的DNA损伤。然而，FANCG和FANCD1/BRCA2在tmz诱导的DNA损伤修复中发挥了显著的重要作用。与ACNU和TMZ细胞敏感性相关的最有效分子靶点是FANCD1/BRCA2。此外，我们发现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。这些发现表明，下调FANCD1/BRCA2可能是增加ACNU和TMZ细胞化学致敏的有效策略。

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.