Distinct and sequential re-replication barriers ensure precise genome duplication

English version

Autoři: Yizhuo Zhou ^aff001; Pedro N. Pozo ^aff002; Seeun Oh ^aff003; Haley M. Stone ^aff001; Jeanette Gowen Cook ^aff001
Působiště autorů: Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United State of America ^aff001; Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United State of America ^aff002; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and the Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United State of America ^aff003; Lineberger Comprehensive Cancer, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United State of America ^aff004
Vyšlo v časopise: Distinct and sequential re-replication barriers ensure precise genome duplication. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008988
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008988

Souhrn

Achieving complete and precise genome duplication requires that each genomic segment be replicated only once per cell division cycle. Protecting large eukaryotic genomes from re-replication requires an overlapping set of molecular mechanisms that prevent the first DNA replication step, the DNA loading of MCM helicase complexes to license replication origins, after S phase begins. Previous reports have defined many such origin licensing inhibition mechanisms, but the temporal relationships among them are not clear, particularly with respect to preventing re-replication in G2 and M phases. Using a combination of mutagenesis, biochemistry, and single cell analyses in human cells, we define a new mechanism that prevents re-replication through hyperphosphorylation of the essential MCM loading protein, Cdt1. We demonstrate that Cyclin A/CDK1 can hyperphosphorylate Cdt1 to inhibit MCM re-loading in G2 phase. The mechanism of inhibition is to block Cdt1 binding to MCM independently of other known Cdt1 inactivation mechanisms such as Cdt1 degradation during S phase or Geminin binding. Moreover, our findings suggest that Cdt1 dephosphorylation at the mitosis-to-G1 phase transition re-activates Cdt1. We propose that multiple distinct, non-redundant licensing inhibition mechanisms act in a series of sequential relays through each cell cycle phase to ensure precise genome duplication.

Klíčová slova:

Cell cycle and cell division – Cyclins – DNA replication – G1 phase – Immunoblotting – Phosphorylation – Synthesis phase – G2 phase

Zdroje

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Článek DAnkrd49 and Bdbt act via Casein kinase Iε to regulate planar polarity in Drosophila

Článek Costly Genes

Článek Hypomodified tRNA in evolutionarily distant yeasts can trigger rapid tRNA decay to activate the general amino acid control response, but with different consequences

Článek Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph