Flaggs G, Plug A W, Dunks K M, Mundt K E, Ford J C, Quiggle M R, Taylor E M, Westphal C H, Ashley T, Hoekstra M F, Carr A M
ICOS Corporation 22021 20th Avenue S.E., Bothell, Washington 98021, USA.
Curr Biol. 1997 Dec 1;7(12):977-86. doi: 10.1016/s0960-9822(06)00417-9.
Checkpoint pathways prevent cell-cycle progression in the event of DNA lesions. Checkpoints are well defined in mitosis, where lesions can be the result of extrinsic damage, and they are critical in meiosis, where DNA breaks are a programmed step in meiotic recombination. In mitotic yeast cells, the Chk1 protein couples DNA repair to the cell-cycle machinery. The Atm and Atr proteins are mitotic cell-cycle proteins that also associate with chromatin during meiotic prophase I. The genetic and regulatory interaction between Atm and mammalian Chk1 appears to be important for integrating DNA-damage repair with cell-cycle arrest.
We have identified structural homologs of yeast Chk1 in human and mouse. Chk1(Hu/Mo) has protein kinase activity and is expressed in the testis. Chk1 accumulates in late zygotene and pachytene spermatocytes and is present along synapsed meiotic chromosomes. Chk1 localizes along the unsynapsed axes of X and Y chromosomes in pachytene spermatocytes. The association of Chk1 with meiotic chromosomes and levels of Chk1 protein depend upon a functional Atm gene product, but Chk1 is not dependent upon p53 for meiosis I functions. Mapping of CHK1 to human chromosomes indicates that the gene is located at 11q22-23, a region marked by frequent deletions and loss of heterozygosity in human tumors.
The Atm-dependent presence of Chk1 in mouse cells and along meiotic chromosomes, and the late pachynema co-localization of Atr and Chk1 on the unsynapsed axes of the paired X and Y chromosomes, suggest that Chk1 acts as an integrator for Atm and Atr signals and may be involved in monitoring the processing of meiotic recombination. Furthermore, mapping of the CHK1 gene to a region of frequent loss of heterozygosity in human tumors at 11q22-23 indicates that the CHK1 gene is a candidate tumor suppressor gene.
检查点通路可在DNA损伤时阻止细胞周期进程。检查点在有丝分裂中定义明确，此时损伤可能是外部损伤的结果，而在减数分裂中它们至关重要，因为DNA断裂是减数分裂重组中的一个程序性步骤。在有丝分裂的酵母细胞中，Chk1蛋白将DNA修复与细胞周期机制联系起来。Atm和Atr蛋白是有丝分裂细胞周期蛋白，在减数分裂前期I也与染色质相关。Atm与哺乳动物Chk1之间的遗传和调控相互作用似乎对于将DNA损伤修复与细胞周期停滞整合起来很重要。
我们在人和小鼠中鉴定出了酵母Chk1的结构同源物。Chk1（Hu/Mo）具有蛋白激酶活性，在睾丸中表达。Chk1在偶线期后期和粗线期精母细胞中积累，并存在于联会的减数分裂染色体上。Chk1定位于粗线期精母细胞中X和Y染色体未联会的轴上。Chk1与减数分裂染色体的关联以及Chk1蛋白水平取决于功能性Atm基因产物，但Chk1在减数分裂I功能方面不依赖于p53。将CHK1定位到人类染色体表明该基因位于11q22 - 23，这是人类肿瘤中频繁发生缺失和杂合性缺失的区域。
小鼠细胞中以及减数分裂染色体上依赖于Atm的Chk1的存在，以及Atr和Chk1在配对的X和Y染色体未联会轴上的粗线期后期共定位，表明Chk1作为Atm和Atr信号的整合者，可能参与监测减数分裂重组的进程。此外，将CHK1基因定位到人类肿瘤中11q22 - 23频繁发生杂合性缺失的区域表明CHK1基因是一个候选肿瘤抑制基因。
