Distinct and sequential re-replication barriers ensure precise genome duplication.
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 loadi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-08-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1008988 |
| _version_ | 1811315794659770368 |
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| author | Yizhuo Zhou Pedro N Pozo Seeun Oh Haley M Stone Jeanette Gowen Cook |
| author_facet | Yizhuo Zhou Pedro N Pozo Seeun Oh Haley M Stone Jeanette Gowen Cook |
| author_sort | Yizhuo Zhou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T11:37:47Z |
| format | Article |
| id | doaj.art-aacfe3a083c94ea783c2504ff8b2327b |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T11:37:47Z |
| publishDate | 2020-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-aacfe3a083c94ea783c2504ff8b2327b2022-12-22T02:48:23ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-08-01168e100898810.1371/journal.pgen.1008988Distinct and sequential re-replication barriers ensure precise genome duplication.Yizhuo ZhouPedro N PozoSeeun OhHaley M StoneJeanette Gowen CookAchieving 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.https://doi.org/10.1371/journal.pgen.1008988 |
| spellingShingle | Yizhuo Zhou Pedro N Pozo Seeun Oh Haley M Stone Jeanette Gowen Cook Distinct and sequential re-replication barriers ensure precise genome duplication. PLoS Genetics |
| title | Distinct and sequential re-replication barriers ensure precise genome duplication. |
| title_full | Distinct and sequential re-replication barriers ensure precise genome duplication. |
| title_fullStr | Distinct and sequential re-replication barriers ensure precise genome duplication. |
| title_full_unstemmed | Distinct and sequential re-replication barriers ensure precise genome duplication. |
| title_short | Distinct and sequential re-replication barriers ensure precise genome duplication. |
| title_sort | distinct and sequential re replication barriers ensure precise genome duplication |
| url | https://doi.org/10.1371/journal.pgen.1008988 |
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