The Institute for Cancer Studies, Department of Oncology, Faculty of Medicine Dentistry and Health Sciences, University of Sheffield, Sheffield, UK.
Oncogene. 2013 Nov 14;32(46):5338-46. doi: 10.1038/onc.2012.627. Epub 2013 Jan 14.
Uveal melanoma (UM) is unique among cancers in displaying reduced endogenous levels of sister chromatid exchange (SCE). Here we demonstrate that FANCD2 expression is reduced in UM and that ectopic expression of FANCD2 increased SCE. Similarly, FANCD2-deficient fibroblasts (PD20) derived from Fanconi anaemia patients displayed reduced spontaneous SCE formation relative to their FANCD2-complemented counterparts, suggesting that this observation is not specific to UM. In addition, spontaneous RAD51 foci were reduced in UM and PD20 cells compared with FANCD2-proficient cells. This is consistent with a model where spontaneous SCEs are the end product of endogenous recombination events and implicates FANCD2 in the promotion of recombination-mediated repair of endogenous DNA damage and in SCE formation during normal DNA replication. In both UM and PD20 cells, low SCE was reversed by inhibiting DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Finally, we demonstrate that both PD20 and UM are sensitive to acetaldehyde, supporting a role for FANCD2 in repair of lesions induced by such endogenous metabolites. Together, these data suggest FANCD2 may promote spontaneous SCE by influencing which double-strand break repair pathway predominates during normal S-phase progression.
葡萄膜黑色素瘤（UM）在显示降低的姐妹染色单体交换（SCE）内源性水平方面在癌症中是独特的。在这里，我们证明 FANCD2 表达在 UM 中降低，并且 FANCD2 的异位表达增加了 SCE。类似地，源自范可尼贫血患者的 FANCD2 缺陷成纤维细胞（PD20）与 FANCD2 互补的对应物相比，显示出降低的自发 SCE 形成，这表明这种观察结果不是 UM 所特有的。此外，与 FANCD2 功能正常的细胞相比，UM 和 PD20 细胞中的自发 RAD51 焦点减少。这与自发 SCE 是内源性重组事件的最终产物的模型一致，并暗示 FANCD2 促进内源性 DNA 损伤的重组介导修复以及正常 DNA 复制过程中的 SCE 形成。在 UM 和 PD20 细胞中，通过抑制 DNA-PKcs（DNA 依赖性蛋白激酶，催化亚基），低 SCE 被逆转。最后，我们证明 PD20 和 UM 都对乙醛敏感，支持 FANCD2 在修复此类内源性代谢物诱导的损伤中的作用。总之，这些数据表明 FANCD2 可能通过影响在正常 S 期进展过程中占主导地位的双链断裂修复途径来促进自发 SCE。
