Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining
Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining
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DOI：
10.1093/hmg/ddi334
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发表时间：
2005-10-15
影响因子：
3.5
通讯作者：
Grompe, M
中科院分区：
文献类型：
--
作者：
Houghtaling, S;Newell, A;Grompe, M
范可尼贫血（FA）是一种多基因隐性遗传疾病，可导致骨髓衰竭和癌症易感性增加。FA患者和小鼠模型的细胞对DNA链间交联（ICL）敏感，FA小鼠对电离辐射（IR）中度敏感。这两种损伤都会导致DNA双链断裂（DSB）。到目前为止，已经确定了11个互补组中的9个基因;然而，FA途径的确切功能仍不清楚。许多蛋白质形成下游蛋白质Fancd 2的单泛素化所必需的核复合物。为了进一步研究FA途径在DSB修复中的作用，我们产生了Fancd 2（-/-）/Prkdc（sc/sc）双突变小鼠。Prkdc（sc/sc）突变小鼠在非同源末端连接（NHEJ）方面存在缺陷，并且对IR诱导的DNA损伤敏感。双突变体动物和原代细胞对IR比任一单突变体更敏感，表明Fancd 2在DSB修复途径中不同于NHEJ。Fancd 2（-/-）/Prkdc（sc/sc）双突变细胞对限制性内切酶产生的DSB也更敏感。Fancd 2在DSB修复中的作用可能解释了FA细胞对辐射的中度敏感性和FA细胞对通过DSB中间体修复的ICL的敏感性。
Fanconi anemia (FA) is a multigenic recessive disease resulting in bone marrow failure and increased cancer susceptibility. Cells from FA patients and mouse models are sensitive to DNA interstrand crosslinks (ICLs) and FA mice are moderately sensitive to ionizing radiation (IR). Both kinds of damage induce DNA double strand breaks (DSBs). To date, nine genes in 11 complementation groups have been identified; however, the precise function of the FA pathway remains unclear. Many of the proteins form a nuclear complex necessary for the mono-ubiquitination of the downstream protein, Fancd2. To further investigate the role of the FA pathway in repair of DSBs, we generated Fancd2(-/-)/Prkdc(sc/sc) double mutant mice. Prkdc(sc/sc) mutant mice have a defect in non-homologous end joining (NHEJ) and are sensitive to IR-induced DNA damage. Double mutant animals and primary cells were more sensitive to IR than either single mutant, suggesting that Fancd2 operates in DSB repair pathway distinct from NHEJ. Fancd2(-/-)/Prkdc(sc/sc) double mutant cells were also more sensitive to DSBs generated by a restriction endonuclease. The role of Fancd2 in DSB repair may account for the moderate sensitivity of FA cells to irradiation and FA cells sensitivity to ICLs that are repaired via a DSB intermediate.