The role of APC/CCdh1 in replication stress and origin of genomic instability
The role of APC/CCdh1 in replication stress and origin of genomic instability
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DOI：
10.1038/onc.2015.367
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发表时间：
2016-06-09
期刊：
影响因子：
8
通讯作者：
Waesch, R.
中科院分区：
文献类型：
--
作者：
Greil, C.;Krohs, J.;Waesch, R.
有人提出，APC/C-Cdh1 通过维持基因组稳定性发挥肿瘤抑制因子的作用。然而，Cdh1 丢失后基因组不稳定的确切性质尚不清楚。利用单细胞的生物化学和活细胞成像，我们发现 Cdh1 敲低 (kd) 会导致底物细胞周期蛋白 A 和 B 的强核稳定性，并解除 DNA 复制动力学的调节。 Cdh1 依赖性 G2 DNA 损伤检查点的恢复不会导致 G2 停滞，但会阻止细胞进入中期，表明这些细胞尽管复制不完全，但仍进入有丝分裂。这会导致 DNA 双链断裂、后期桥、胞质分裂缺陷和四倍体化。四倍体细胞是 Cdh1-kd 后多余中心体的来源，导致多极有丝分裂或中心体聚集，进而导致裂隙附着和滞后染色体。尽管其中一些事件在有丝分裂期间导致细胞凋亡，但存活的细胞可能会积累染色体畸变。
It has been proposed that the APC/C-Cdh1 functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.