Drosophila homologs of FANCD2 and FANCL function in DNA repair
Drosophila homologs of FANCD2 and FANCL function in DNA repair
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DOI：
10.1016/j.dnarep.2006.05.044
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发表时间：
2006-11-08
期刊：
影响因子：
3.8
通讯作者：
Bale, Allen E.
中科院分区：
文献类型：
--
作者：
Marek, Lorri R.;Bale, Allen E.
范可尼贫血（FA）是一种遗传异质性疾病，其特征是发育缺陷、进行性骨髓衰竭和癌症易感性。来自 FA 患者的细胞表现出自发的染色体畸变和对交联剂的过敏，表明 DNA 修复存在细胞缺陷。在12个FA基因中，只有FANCD2、FANCL和FANCM具有果蝇同源物。鉴于人类和果蝇 FA 途径之间的差异，果蝇同源物是否在 DNA 修复中发挥作用尚不清楚。在这里，我们报告果蝇 FANCD2 或 FANCL 的敲低会导致对交联剂的特异性超敏反应。进一步分析表明，FANCD2 和 FANCL 在线性途径中发挥作用，其中 FANCL 对于 FANCD2 的单泛素化是必需的。 FANCD2突变体在电离辐射诱导的S期检查点中也表现出相同的缺陷，这在缺乏该基因的哺乳动物细胞中可见。最后，在失活突变测定中，FANCD2 突变体对氮芥的反应具有升高的突变率，表明这些果蝇是高度可变的。综上所述，这些数据表明果蝇 FANCD2 和 FANCL 在 DNA 修复中发挥着关键作用。由于缺乏其他 FA 基因，进一步的研究将确定保守的 FA 基因是否作为最小机制发挥作用，或者是否有其他基因参与果蝇 FA 途径。 (c) 2006 Elsevier B.V. 保留所有权利。
Fanconi anemia (FA) is a genetically heterogeneous disease characterized by developmental defects, progressive bone marrow failure and cancer susceptibility. Cells derived from patients with FA show spontaneous chromosomal aberrations and hypersensitivity to cross-linking agents, indicating a cellular defect in DNA repair. Among the 12 FA genes, only FANCD2, FANCL and FANCM have Drosophila homologs. Given this difference between the human and Drosophila FA pathways, it is unknown whether the fly homologs function in DNA repair. Here, we report that knockdown of Drosophila FANCD2 or FANCL leads to specific hypersensitivity to cross-linking agents. Further analysis revealed that FANCD2 and FANCL function in a linear pathway with FANCL being necessary for the monoubiquitination of FANCD2. FANCD2 mutants also exhibited the same defect in the ionizing radiation-inducible S-phase checkpoint that is seen in mammalian cells deficient for this gene. Finally, in an assay for inactivating mutations, FANCD2 mutants have an elevated mutation rate in response to nitrogen mustard, indicating that these flies are hypermutable. Taken together, these data demonstrate that Drosophila FANCD2 and FANCL play a critical role in DNA repair. Because of the lack of other FA genes, further studies will determine whether the conserved FA genes function as the minimal machinery or whether additional genes are involved in the Drosophila FA pathway. (c) 2006 Elsevier B.V. All rights reserved.