The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction.
The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction.
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DOI：
10.1093/nar/gkp262
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发表时间：
2009-07
影响因子：
14.9
通讯作者：
Miyagawa K
中科院分区：
文献类型：
--
作者：
Katsura M;Tsuruga T;Date O;Yoshihara T;Ishida M;Tomoda Y;Okajima M;Takaku M;Kurumizaka H;Kinomura A;Mishima HK;Miyagawa K
Rad 51 C是脊椎动物中由五个Rad 51旁系同源物形成的两个复合物的中心组分。这些复合物参与通过同源重组修复DNA双链断裂。尽管有越来越多的证据表明旁系同源物可以通过控制中心体的完整性来防止非整倍性，但Rad 51 C在维持染色体稳定性方面的作用仍然不清楚。在这里，我们证明，Rad 51 C缺陷导致两个中心体畸变的ATR-Chk 1依赖的方式和人类细胞中的非整倍体增加。虽然据报道，Rad 51 C缺陷不会导致仓鼠细胞间期的中心体畸变，但在Rad 51 C功能障碍的HCT 116细胞中观察到间期的这种畸变。咖啡因处理和下调ATR，但不是ATM，减少突变细胞的中心体畸变的频率。在HT 1080细胞中通过RNA干扰来沉默Rad 51 C导致类似的畸变。用Chk 1抑制剂处理和沉默Chk 1也降低了HCT 116突变体的频率。突变体中Chk 1在γ H2 AX中心体和核灶的积累增加。此外，突变细胞具有较高的非整倍体频率。这些发现表明，ATR-Chk 1通路在Rad 51 C功能障碍诱导的中心体畸变增加中起作用。
Rad51C is a central component of two complexes formed by five Rad51 paralogs in vertebrates. These complexes are involved in repairing DNA double-strand breaks through homologous recombination. Despite accumulating evidence suggesting that the paralogs may prevent aneuploidy by controlling centrosome integrity, Rad51C's role in maintaining chromosome stability remains unclear. Here we demonstrate that Rad51C deficiency leads to both centrosome aberrations in an ATR-Chk1-dependent manner and increased aneuploidy in human cells. While it was reported that Rad51C deficiency did not cause centrosome aberrations in interphase in hamster cells, such aberrations were observed in interphase in HCT116 cells with Rad51C dysfunction. Caffeine treatment and down-regulation of ATR, but not that of ATM, reduced the frequency of centrosome aberrations in the mutant cells. Silencing of Rad51C by RNA interference in HT1080 cells resulted in similar aberrations. Treatment with a Chk1 inhibitor and silencing of Chk1 also reduced the frequency in HCT116 mutants. Accumulation of Chk1 at the centrosome and nuclear foci of γH2AX were increased in the mutants. Moreover, the mutant cells had a higher frequency of aneuploidy. These findings indicate that the ATR-Chk1 pathway plays a role in increased centrosome aberrations induced by Rad51C dysfunction.
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