CELL CYCLE CHECKPOINTS IN THE XENOPUS EMBRYO

真核细胞周期中的检查点通过在DNA受损或不完全复制时阻止细胞周期来维持基因组的完整性。 检查点途径汇聚在细胞周期蛋白依赖性激酶（Cdks）的活性上，Cdks是催化细胞周期进程的酶。 非洲爪蟾的早期胚胎细胞周期提供了罕见的无检查点的非病理性细胞分裂的例子。 受精后，非洲爪蟾卵开始12个快速和同步的细胞周期，在DNA复制和有丝分裂之间振荡，没有生长，间隙期或检查点。 当DNA受损或DNA复制受阻时，这些早期细胞周期会"不受控制"地进行。 第12次卵裂的完成标志着中胚转变（MBT）。 在MBT，胚胎基因表达开始，细胞周期重塑，延长，因为它获得了典型的成年细胞周期的差距阶段和检查点。该项目将研究XChk 1在非洲爪蟾胚胎发育过程中的作用。 XChk 1与哺乳动物和酵母Chk 1同源，其抑制Cdks以维持细胞周期停滞。XChk1也与Grp1同源，Grp1在果蝇发育期间对MBT进行计时。 XChk1的功能将在非洲爪蟾胚胎的重塑细胞周期进行研究。 具体的目标是调查1）当XChk1信号开始运作，2）在DNA损伤和DNA复制检查点中对XChk1的需求，3）XChk1与细胞凋亡发育程序之间的关系，4）XChk1在MBT定时中的作用，5）XChk1信号的靶点。非洲爪蟾的胚胎细胞分裂从快速细胞周期重塑为受调节的细胞周期，提供了一个独特丰富的系统来研究检查点的参与。 更好地了解青蛙胚胎发生过程中介导细胞周期检查点的信号通路可能有助于我们调节其他非典型细胞周期。 这些包括癌症的旺盛细胞周期，衰老和衰老的失败细胞周期，以及传染病的篡夺细胞周期。

Checkpoints in the eukaryotic cell cycle maintain the integrity of the genome by arresting the cell cycle when DNA is damaged or incompletely replicated. Checkpoint pathways converge upon the activities of cyclin-dependent kinases (Cdks), enzymes that catalyze cell cycle progression. Early embryonic cell cycles of the frog Xenopus laevis provide rare examples of non-pathological cell divisions that lack checkpoints. Following fertilization, the Xenopus egg begins twelve rapid and synchronous cell cycles that oscillate between DNA replication and mitosis without growth, gap phases, or checkpoints. These early cell cycles proceed "unchecked" when DNA is damaged or DNA replication is blocked. Completion of the twelfth cleavage marks the midblastula transition (MBT). At the MBT, embryonic gene expression begins, and the cell cycle remodels, lengthening as it acquires the gap phases and checkpoints of a typical adult cell cycle. The proposed project will investigate the role of XChk1 during embryogenesis of Xenopus. XChk1 is homologous to mammalian and yeast Chk1, which inactivate Cdks to maintain cell cycle arrest. XChk1 is also homologous to Grp1, which functions in timing the MBT during Drosophila development. XChk1 function will be investigated during the remodeling cell cycles of the Xenopus embryo. Specific aims are to investigate 1) when XChk1 signaling becomes operational, 2) the requirement for XChk1 in DNA damage and DNA replication checkpoints, and 3) the relationship between XChk1 and a developmental program of apoptosis, 4) the role of XChk1 in timing the MBT, and 5) the targets of XChk1 signaling. The embryonic cell divisions of Xenopus, which remodel from rapid to regulated cell cycles, provide a uniquely rich system in which to investigate the engagement of checkpoints. A better understanding of the signaling pathways that mediate cell cycle checkpoints during frog embryogenesis may help us to modulate other atypical cell cycles. These include the exuberant cell cycles of cancer, the failing cell cycles of aging and senescence, and the usurped cell cycles of infectious disease.