The Wu Lab
Genome duplication is a critical part of the cell cycle that is highly regulated to ensure proper cell growth and proliferation. The distribution of the sites of initiation of DNA replication, or origins, across the genome changes during development and differentiation, suggesting that the program of genome duplication is highly controlled. Alterations in the replication pattern have also been observed in a number of pathologies, such as in cancers. However, the fundamental features driving origin selection and the importance of using specific replication programs remain surprisingly unknown. The research in our laboratory aims to study different aspects of genome duplication and maintenance using the fission yeast Schizosaccharomyces pombe as a model system.
|CDK activity provides temporal and quantitative cues for organizing genome duplication
Perrot A, Millington CL, Gomez-Escoda B, Schausi-Tiffoche D, and Wu PY
PLOS Genetics 14(2):e1007214 (February 2018)
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In eukaryotes, the spatial and temporal organization of genome duplication gives rise to distinctive profiles of replication origin usage along the chromosomes. While it has become increasingly clear that these programs are important for cellular physiology, the mechanisms by which they are determined and modulated remain elusive. Replication initiation requires the function of cyclin-dependent kinases (CDKs), which associate with various cyclin partners to drive cell proliferation. Surprisingly, although we possess detailed knowledge of the CDK regulators and targets that are crucial for origin activation, little is known about whether CDKs play a critical role in establishing the genome-wide pattern of origin selection. We have addressed this question in the fission yeast, taking advantage of a simplified cell cycle network in which cell proliferation is driven by a single cyclin-CDK module. This system allows us to precisely control CDK activity in vivo using chemical genetics. First, in contrast to previous reports, our results clearly show that distinct cyclin-CDK pairs are not essential for regulating specific subsets of origins and for establishing a normal replication program. Importantly, we then demonstrate that the timing at which CDK activity reaches the S phase threshold is critical for the organization of replication in distinct efficiency domains, while the level of CDK activity at the onset of S phase is a dose-dependent modulator of overall origin efficiencies. Our study therefore implicates these different aspects of CDK regulation as versatile mechanisms for shaping the architecture of DNA replication across the genome.
|Replication origin selection regulates the distribution of meiotic recombination
Wu PY and Nurse P
Molecular Cell 53:655-662 (February 2014)
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The program of DNA replication, defined by the temporal and spatial pattern of origin activation, is altered during development and in cancers. However, whether changes in origin usage play a role in regulating specific biological processes remains unknown. We investigated the consequences of modifying origin selection on meiosis in fission yeast. Genome-wide changes in the replication program of premeiotic S phase do not affect meiotic progression, indicating that meiosis neither activates nor requires a particular origin pattern. In contrast, local changes in origin efficiencies between different replication programs lead to changes in Rad51 recombination factor binding and recombination frequencies in these domains. We observed similar results for Rad51 when changes in efficiencies were generated by directly targeting expression of the Cdc45 replication factor. We conclude that origin selection is a key determinant for organizing meiotic recombination, providing evidence that genome-wide modifications in replication program can modulate cellular physiology.
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