The consequences of differential origin licensing dynamics in distinct chromatin environments
Eukaryotic chromosomes contain regions of varying accessibility, yet DNA replication factors must access all regions. The first replication step is loading MCM complexes to license replication origins during the G1 cell cycle phase. It is not yet known how mammalian MCM complexes are adequately dist...
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ftpubmed:oai:pubmedcentral.nih.gov:9508807 2023-05-15T17:53:52+02:00 The consequences of differential origin licensing dynamics in distinct chromatin environments Mei, Liu Kedziora, Katarzyna M Song, Eun-Ah Purvis, Jeremy E Cook, Jeanette Gowen 2022-01-26 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508807/ http://www.ncbi.nlm.nih.gov/pubmed/35079814 https://doi.org/10.1093/nar/gkac003 en eng Oxford University Press http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508807/ http://www.ncbi.nlm.nih.gov/pubmed/35079814 http://dx.doi.org/10.1093/nar/gkac003 © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com CC-BY-NC Nucleic Acids Res NAR Breakthrough Article Text 2022 ftpubmed https://doi.org/10.1093/nar/gkac003 2022-10-02T00:41:09Z Eukaryotic chromosomes contain regions of varying accessibility, yet DNA replication factors must access all regions. The first replication step is loading MCM complexes to license replication origins during the G1 cell cycle phase. It is not yet known how mammalian MCM complexes are adequately distributed to both accessible euchromatin regions and less accessible heterochromatin regions. To address this question, we combined time-lapse live-cell imaging with immunofluorescence imaging of single human cells to quantify the relative rates of MCM loading in euchromatin and heterochromatin throughout G1. We report here that MCM loading in euchromatin is faster than that in heterochromatin in early G1, but surprisingly, heterochromatin loading accelerates relative to euchromatin loading in middle and late G1. This differential acceleration allows both chromatin types to begin S phase with similar concentrations of loaded MCM. The different loading dynamics require ORCA-dependent differences in origin recognition complex distribution. A consequence of heterochromatin licensing dynamics is that cells experiencing a truncated G1 phase from premature cyclin E expression enter S phase with underlicensed heterochromatin, and DNA damage accumulates preferentially in heterochromatin in the subsequent S/G2 phase. Thus, G1 length is critical for sufficient MCM loading, particularly in heterochromatin, to ensure complete genome duplication and to maintain genome stability. Text Orca PubMed Central (PMC) Nucleic Acids Research 50 17 9601 9620 |
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NAR Breakthrough Article |
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NAR Breakthrough Article Mei, Liu Kedziora, Katarzyna M Song, Eun-Ah Purvis, Jeremy E Cook, Jeanette Gowen The consequences of differential origin licensing dynamics in distinct chromatin environments |
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NAR Breakthrough Article |
description |
Eukaryotic chromosomes contain regions of varying accessibility, yet DNA replication factors must access all regions. The first replication step is loading MCM complexes to license replication origins during the G1 cell cycle phase. It is not yet known how mammalian MCM complexes are adequately distributed to both accessible euchromatin regions and less accessible heterochromatin regions. To address this question, we combined time-lapse live-cell imaging with immunofluorescence imaging of single human cells to quantify the relative rates of MCM loading in euchromatin and heterochromatin throughout G1. We report here that MCM loading in euchromatin is faster than that in heterochromatin in early G1, but surprisingly, heterochromatin loading accelerates relative to euchromatin loading in middle and late G1. This differential acceleration allows both chromatin types to begin S phase with similar concentrations of loaded MCM. The different loading dynamics require ORCA-dependent differences in origin recognition complex distribution. A consequence of heterochromatin licensing dynamics is that cells experiencing a truncated G1 phase from premature cyclin E expression enter S phase with underlicensed heterochromatin, and DNA damage accumulates preferentially in heterochromatin in the subsequent S/G2 phase. Thus, G1 length is critical for sufficient MCM loading, particularly in heterochromatin, to ensure complete genome duplication and to maintain genome stability. |
format |
Text |
author |
Mei, Liu Kedziora, Katarzyna M Song, Eun-Ah Purvis, Jeremy E Cook, Jeanette Gowen |
author_facet |
Mei, Liu Kedziora, Katarzyna M Song, Eun-Ah Purvis, Jeremy E Cook, Jeanette Gowen |
author_sort |
Mei, Liu |
title |
The consequences of differential origin licensing dynamics in distinct chromatin environments |
title_short |
The consequences of differential origin licensing dynamics in distinct chromatin environments |
title_full |
The consequences of differential origin licensing dynamics in distinct chromatin environments |
title_fullStr |
The consequences of differential origin licensing dynamics in distinct chromatin environments |
title_full_unstemmed |
The consequences of differential origin licensing dynamics in distinct chromatin environments |
title_sort |
consequences of differential origin licensing dynamics in distinct chromatin environments |
publisher |
Oxford University Press |
publishDate |
2022 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508807/ http://www.ncbi.nlm.nih.gov/pubmed/35079814 https://doi.org/10.1093/nar/gkac003 |
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op_source |
Nucleic Acids Res |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508807/ http://www.ncbi.nlm.nih.gov/pubmed/35079814 http://dx.doi.org/10.1093/nar/gkac003 |
op_rights |
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
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CC-BY-NC |
op_doi |
https://doi.org/10.1093/nar/gkac003 |
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Nucleic Acids Research |
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50 |
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17 |
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9620 |
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