Atm-dependent interactions of a mammalian Chk1 homolog with meiotic chromosomes
Atm-dependent interactions of a mammalian Chk1 homolog with meiotic chromosomes
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DOI：
10.1016/s0960-9822(06)00417-9
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发表时间：
1997-12-01
期刊：
影响因子：
9.2
通讯作者：
Carr, AM
中科院分区：
文献类型：
--
作者：
Flaggs, G;Plug, AW;Carr, AM
背景：在DNA损伤的情况下，检查点通路阻止细胞周期的进展，检查点在有丝分裂中被很好地定义，在有丝分裂中，损伤可以是外部损伤的结果，它们在减数分裂中是关键的，在减数分裂中，DNA断裂是减数分裂重组中的一个程序化步骤。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结合起来。ATM和ATR蛋白是有丝分裂的细胞周期蛋白，在减数分裂前期1也与染色质相关。ARM和哺乳动物Chk1之间的遗传和调控相互作用对于整合DNA损伤修复和细胞周期抑制是重要的。结果：我们在人和小鼠中鉴定了酵母Chk1的结构同源基因。Chk1(Hu/Mo)具有蛋白激酶活性，在睾丸中表达。Chk1在晚期合线期和粗线期精母细胞中聚集，并沿联会的减数分裂染色体存在，在粗线期精母细胞中Chk1沿X和Y染色体的非突触轴定位。Chk1与减数分裂染色体和Chk1蛋白水平的关联依赖于一个功能性的ATM基因产物，但Chk1的减数分裂I功能不依赖于p53。将Chk1映射到人类染色体上表明，Chk1位于11q22-23，这是一个在人类肿瘤中频繁缺失和杂合性丧失的区域。结论：Chk1在小鼠细胞和减数分裂染色体上依赖ATM的存在，以及ATR和Chk1在配对的X和Y染色体的未突触轴上的晚期共定位，提示Chk1作为ATM和ATR信号的整合子，可能参与监测减数分裂重组的过程。此外，将CHK1基因定位到人类肿瘤中11q22-23的杂合性缺失区域，表明CHK1基因是一个候选的肿瘤抑制基因。
Background: 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 1. The genetic and regulatory interaction between Arm and mammalian Chk1 appears to be important for integrating DNA-damage repair with cell-cycle arrest.Results: 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.Conclusions: 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.