Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM
Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM
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DOI：
10.1038/sj.emboj.7600534
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发表时间：
2005-01-26
期刊：
影响因子：
11.4
通讯作者：
Takata, M
中科院分区：
文献类型：
--
作者：
Hirano, S;Yamamoto, K;Takata, M
一些停滞的复制分叉的重新启动事件导致姐妹染色单体交换(SCE)，这是同源重组(HR)修复与交换的结果。BLM解旋酶的缺失或跨损伤合成(TLS)的缺陷会导致姐妹染色单体交换频率升高。我们发现，在Fanconi贫血(FA)基因FANCC缺陷的鸡DT40细胞中，自发姐妹染色单体交换水平升高了近2倍。为了研究SCE升高的机制，我们在缺乏RAD51 Paralog XRCC3、TLS因子RAD18或BLM的细胞中删除了FANCC。FANCC细胞姐妹染色单体交换率的增加需要Xrcc3，而Fancc/rad18双突变体的姐妹染色单体交换率高于任一单突变体。出乎意料的是，FANCC/BLm突变体的姐妹染色单体交换频率与BLm细胞相似，提示FANCC和BLm之间存在功能连锁。此外，在人和鸡的FANC或FANCD2细胞中，MMC诱导的GFP-BLM核焦点的形成都受到严重影响。我们的细胞存活数据表明，在交联链修复过程中，FA蛋白有助于HR，而不是全局TLS。
Some of the restarting events of stalled replication forks lead to sister chromatid exchange ( SCE) as a result of homologous recombination (HR) repair with crossing over. The rate of SCE is elevated by the loss of BLM helicase or by a defect in translesion synthesis (TLS). We found that spontaneous SCE levels were elevated similar to2-fold in chicken DT40 cells deficient in Fanconi anemia ( FA) gene FANCC. To investigate the mechanism of the elevated SCE, we deleted FANCC in cells lacking Rad51 paralog XRCC3, TLS factor RAD18, or BLM. The increased SCE in fancc cells required Xrcc3, whereas the fancc/rad18 double mutant exhibited higher SCE than either single mutant. Unexpectedly, SCE in the fancc/blm mutant was similar to that in blm cells, indicating functional linkage between FANCC and BLM. Furthermore, MMC-induced formation of GFP-BLM nuclear foci was severely compromised in both human and chicken fancc or fancd2 cells. Our cell survival data suggest that the FA proteins serve to facilitate HR, but not global TLS, during crosslink repair.