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.
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