Distinct and sequential re-replication barriers ensure precise genome duplication


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: 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


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