Abstract
During metazoan development, the cell cycle is remodelled to coordinate proliferation with differentiation. Developmental cues cause dramatic changes in the number and timing of replication initiation events, but the mechanisms and physiological importance of such changes are poorly understood. Cyclin-dependent kinases (CDKs) are important for regulating S-phase length in many metazoa, and here we show in the nematode Caenorhabditis elegans that an essential function of CDKs during early embryogenesis is to regulate the interactions between three replication initiation factors SLD-3, SLD-2 and MUS-101 (Dpb11/TopBP1). Mutations that bypass the requirement for CDKs to generate interactions between these factors is partly sufficient for viability in the absence of Cyclin E, demonstrating that this is a critical embryonic function of this Cyclin. Both SLD-2 and SLD-3 are asymmetrically localised in the early embryo and the levels of these proteins inversely correlate with S-phase length. We also show that SLD-2 asymmetry is determined by direct interaction with the polarity protein PKC-3. This study explains an essential function of CDKs for replication initiation in a metazoan and provides the first direct molecular mechanism through which polarization of the embryo is coordinated with DNA replication initiation factors.
Highlights
Eukaryotes replicate their genomes from multiple origins that fire throughout S-phase of the cell cycle
The nematode C. elegans is an excellent system to study the role of cell cycle changes during animal development
In this study we show that phospho-mimicking mutations at the critical Cyclin-dependent kinases (CDKs) consensus sites in sld-2 and sld-3 are sufficient to fulfil at least in part the essential functions of cyclin E in C. elegans
Summary
Eukaryotes replicate their genomes from multiple origins that fire throughout S-phase of the cell cycle. Programmed changes in the number, timing and position of origin firing occur during differentiation and development across many metazoa [1]. Different cell types exhibit dramatic changes in the rate of S-phase and the timing with which different parts of the genome are replicated. With its highly stereotypical cell divisions, the early C. elegans embryo provides an ideal system to study the role of cell cycle control during development. As early as the second embryonic division, polarity cues generate cells with different S-phase lengths [2,3]. How CDKs control embryonic cell cycle length is not known
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