DNA replication licensing in somatic and germ cells
DNA replication licensing in somatic and germ cells
复制标题
DOI：
10.1242/jcs.01503
复制
发表时间：
2004-11-15
影响因子：
4
通讯作者：
Williams, GH
中科院分区：
文献类型：
--
作者：
Eward, KL;Obermann, EC;Williams, GH
DNA复制(或起源)许可制度确保在每个细胞周期中精确复制基因组，是后生动物细胞增殖的强大调节器。对酵母、黑腹果蝇和非洲爪哇的研究已经描述了构成许可系统的分子机制，但这一重要的进化保守途径如何在智人中受到调控仍有待确定。我们研究了人类体细胞和生殖细胞中起源许可因子CDC6、CDT1、McM2和Gminin的调节。CDC6和CDT1通过将解开DNA螺旋所需的McM2-7复合体装载到染色体起点上，在DNA复制起始过程中发挥着重要作用。双子座是原产地许可的抑制者，阻止McM2-7加载到原产地。我们的研究表明，在体细胞自我更新系统的增殖-分化转换过程中，CDC6、CDT1和McM2在协调生长过程中起着核心作用，并且在初级卵母细胞中，CDC6的表达是获得复制能力的限速因素。与之形成鲜明对比的是，我们发现雄配子发生过程中的增殖控制与CDC6或McM2无关，但似乎与负调控因子Ginin协调，而CDT1在后期前期成为限速因子。我们的数据表明，在减数分裂I过程中，抑制起源许可和防止不及时的DNA合成的机制具有显著的性别二型性，这意味着双子座在维持雄性生殖系基因组的完整性方面发挥了关键作用。
The DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.