Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery in C. elegans

English version

Autoři: Vincent Gaggioli ^aff001; Manuela R. Kieninger ^aff001; Anna Klucnika ^aff001; Richard Butler ^aff001; Philip Zegerman ^aff001
Působiště autorů: Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Cambridge, United Kingdom ^aff001; Department of Genetics, University of Cambridge, United Kingdom ^aff002; Department of Biochemistry, University of Cambridge, United Kingdom ^aff003
Vyšlo v časopise: Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery in C. elegans. PLoS Genet 16(12): e1008948. doi:10.1371/journal.pgen.1008948
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008948

Souhrn

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.

Klíčová slova:

Caenorhabditis elegans – Cell cycle and cell division – Cell polarity – Cyclins – DNA replication – Phosphorylation – RNA interference – Synthesis phase

Zdroje

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