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PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle
Replication stress and DNA damage stall replication forks and impede genome synthesis. During S phase, damage tolerance pathways allow lesion bypass to ensure efficient genome duplication. One such pathway is repriming, mediated by Primase-Polymerase (PrimPol) in human cells. However, the mechanisms...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641930/ https://www.ncbi.nlm.nih.gov/pubmed/34860556 http://dx.doi.org/10.1126/sciadv.abh1004 |
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author | Bailey, Laura J. Teague, Rebecca Kolesar, Peter Bainbridge, Lewis J. Lindsay, Howard D. Doherty, Aidan J. |
author_facet | Bailey, Laura J. Teague, Rebecca Kolesar, Peter Bainbridge, Lewis J. Lindsay, Howard D. Doherty, Aidan J. |
author_sort | Bailey, Laura J. |
collection | PubMed |
description | Replication stress and DNA damage stall replication forks and impede genome synthesis. During S phase, damage tolerance pathways allow lesion bypass to ensure efficient genome duplication. One such pathway is repriming, mediated by Primase-Polymerase (PrimPol) in human cells. However, the mechanisms by which PrimPol is regulated are poorly understood. Here, we demonstrate that PrimPol is phosphorylated by Polo-like kinase 1 (PLK1) at a conserved residue between PrimPol’s RPA binding motifs. This phosphorylation is differentially modified throughout the cell cycle, which prevents aberrant recruitment of PrimPol to chromatin. Phosphorylation can also be delayed and reversed in response to replication stress. The absence of PLK1-dependent regulation of PrimPol induces phenotypes including chromosome breaks, micronuclei, and decreased survival after treatment with camptothecin, olaparib, and UV-C. Together, these findings establish that deregulated repriming leads to genomic instability, highlighting the importance of regulating this damage tolerance pathway following fork stalling and throughout the cell cycle. |
format | Online Article Text |
id | pubmed-8641930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-86419302021-12-13 PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle Bailey, Laura J. Teague, Rebecca Kolesar, Peter Bainbridge, Lewis J. Lindsay, Howard D. Doherty, Aidan J. Sci Adv Biomedicine and Life Sciences Replication stress and DNA damage stall replication forks and impede genome synthesis. During S phase, damage tolerance pathways allow lesion bypass to ensure efficient genome duplication. One such pathway is repriming, mediated by Primase-Polymerase (PrimPol) in human cells. However, the mechanisms by which PrimPol is regulated are poorly understood. Here, we demonstrate that PrimPol is phosphorylated by Polo-like kinase 1 (PLK1) at a conserved residue between PrimPol’s RPA binding motifs. This phosphorylation is differentially modified throughout the cell cycle, which prevents aberrant recruitment of PrimPol to chromatin. Phosphorylation can also be delayed and reversed in response to replication stress. The absence of PLK1-dependent regulation of PrimPol induces phenotypes including chromosome breaks, micronuclei, and decreased survival after treatment with camptothecin, olaparib, and UV-C. Together, these findings establish that deregulated repriming leads to genomic instability, highlighting the importance of regulating this damage tolerance pathway following fork stalling and throughout the cell cycle. American Association for the Advancement of Science 2021-12-03 /pmc/articles/PMC8641930/ /pubmed/34860556 http://dx.doi.org/10.1126/sciadv.abh1004 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Bailey, Laura J. Teague, Rebecca Kolesar, Peter Bainbridge, Lewis J. Lindsay, Howard D. Doherty, Aidan J. PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle |
title | PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle |
title_full | PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle |
title_fullStr | PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle |
title_full_unstemmed | PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle |
title_short | PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle |
title_sort | plk1 regulates the primpol damage tolerance pathway during the cell cycle |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641930/ https://www.ncbi.nlm.nih.gov/pubmed/34860556 http://dx.doi.org/10.1126/sciadv.abh1004 |
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