Rapid DNA replication origin licensing protects stem cell pluripotency
Complete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/30473 |
| _version_ | 1811252936896937984 |
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| author | Jacob Peter Matson Raluca Dumitru Philip Coryell Ryan M Baxley Weili Chen Kirk Twaroski Beau R Webber Jakub Tolar Anja-Katrin Bielinsky Jeremy E Purvis Jeanette Gowen Cook |
| author_facet | Jacob Peter Matson Raluca Dumitru Philip Coryell Ryan M Baxley Weili Chen Kirk Twaroski Beau R Webber Jakub Tolar Anja-Katrin Bielinsky Jeremy E Purvis Jeanette Gowen Cook |
| author_sort | Jacob Peter Matson |
| collection | DOAJ |
| description | Complete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single-cell analyses, we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance. |
| first_indexed | 2024-04-12T16:42:19Z |
| format | Article |
| id | doaj.art-6189178fb0c5476f957396fdb2db480c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:42:19Z |
| publishDate | 2017-11-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-6189178fb0c5476f957396fdb2db480c2022-12-22T03:24:43ZengeLife Sciences Publications LtdeLife2050-084X2017-11-01610.7554/eLife.30473Rapid DNA replication origin licensing protects stem cell pluripotencyJacob Peter Matson0https://orcid.org/0000-0002-9375-1676Raluca Dumitru1Philip Coryell2Ryan M Baxley3Weili Chen4Kirk Twaroski5Beau R Webber6Jakub Tolar7https://orcid.org/0000-0002-0957-4380Anja-Katrin Bielinsky8https://orcid.org/0000-0003-1783-619XJeremy E Purvis9https://orcid.org/0000-0002-6963-0524Jeanette Gowen Cook10https://orcid.org/0000-0003-0849-7405Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, United StatesHuman Pluripotent Stem Cell Core Facility, The University of North Carolina, Chapel Hill, United StatesDepartment of Genetics, The University of North Carolina, Chapel Hill, United StatesDepartment of Biochemistry, Molecular Biology, and Biophysics, The University of Minnesota, Minneapolis, United StatesStem Cell Institute, University of Minnesota, Minnesota, United StatesStem Cell Institute, University of Minnesota, Minnesota, United StatesStem Cell Institute, University of Minnesota, Minnesota, United StatesStem Cell Institute, University of Minnesota, Minnesota, United StatesDepartment of Biochemistry, Molecular Biology, and Biophysics, The University of Minnesota, Minneapolis, United StatesDepartment of Genetics, The University of North Carolina, Chapel Hill, United States; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, United StatesDepartment of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, United States; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, United StatesComplete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single-cell analyses, we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.https://elifesciences.org/articles/30473cell cycledifferentiationMCMsingle cell analysisG1Cdt1 |
| spellingShingle | Jacob Peter Matson Raluca Dumitru Philip Coryell Ryan M Baxley Weili Chen Kirk Twaroski Beau R Webber Jakub Tolar Anja-Katrin Bielinsky Jeremy E Purvis Jeanette Gowen Cook Rapid DNA replication origin licensing protects stem cell pluripotency eLife cell cycle differentiation MCM single cell analysis G1 Cdt1 |
| title | Rapid DNA replication origin licensing protects stem cell pluripotency |
| title_full | Rapid DNA replication origin licensing protects stem cell pluripotency |
| title_fullStr | Rapid DNA replication origin licensing protects stem cell pluripotency |
| title_full_unstemmed | Rapid DNA replication origin licensing protects stem cell pluripotency |
| title_short | Rapid DNA replication origin licensing protects stem cell pluripotency |
| title_sort | rapid dna replication origin licensing protects stem cell pluripotency |
| topic | cell cycle differentiation MCM single cell analysis G1 Cdt1 |
| url | https://elifesciences.org/articles/30473 |
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