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Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication
Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly underst...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506991/ https://www.ncbi.nlm.nih.gov/pubmed/32705708 http://dx.doi.org/10.15252/embj.2019104185 |
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author | Lerner, Leticia K Holzer, Sandro Kilkenny, Mairi L Šviković, Saša Murat, Pierre Schiavone, Davide Eldridge, Cara B Bittleston, Alice Maman, Joseph D Branzei, Dana Stott, Katherine Pellegrini, Luca Sale, Julian E |
author_facet | Lerner, Leticia K Holzer, Sandro Kilkenny, Mairi L Šviković, Saša Murat, Pierre Schiavone, Davide Eldridge, Cara B Bittleston, Alice Maman, Joseph D Branzei, Dana Stott, Katherine Pellegrini, Luca Sale, Julian E |
author_sort | Lerner, Leticia K |
collection | PubMed |
description | Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly understood. Here, we show that a core component of the fork protection complex in the eukaryotic replisome, Timeless, harbours in its C‐terminal region a previously unappreciated DNA‐binding domain that exhibits specific binding to G‐quadruplex (G4) DNA structures. We show that this domain contributes to maintaining processive replication through G4‐forming sequences, and exhibits partial redundancy with an adjacent PARP‐binding domain. Further, this function of Timeless requires interaction with and activity of the helicase DDX11. Loss of both Timeless and DDX11 causes epigenetic instability at G4‐forming sequences and DNA damage. Our findings indicate that Timeless contributes to the ability of the replisome to sense replication‐hindering G4 formation and ensures the prompt resolution of these structures by DDX11 to maintain processive DNA synthesis. |
format | Online Article Text |
id | pubmed-7506991 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75069912020-09-28 Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication Lerner, Leticia K Holzer, Sandro Kilkenny, Mairi L Šviković, Saša Murat, Pierre Schiavone, Davide Eldridge, Cara B Bittleston, Alice Maman, Joseph D Branzei, Dana Stott, Katherine Pellegrini, Luca Sale, Julian E EMBO J Articles Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly understood. Here, we show that a core component of the fork protection complex in the eukaryotic replisome, Timeless, harbours in its C‐terminal region a previously unappreciated DNA‐binding domain that exhibits specific binding to G‐quadruplex (G4) DNA structures. We show that this domain contributes to maintaining processive replication through G4‐forming sequences, and exhibits partial redundancy with an adjacent PARP‐binding domain. Further, this function of Timeless requires interaction with and activity of the helicase DDX11. Loss of both Timeless and DDX11 causes epigenetic instability at G4‐forming sequences and DNA damage. Our findings indicate that Timeless contributes to the ability of the replisome to sense replication‐hindering G4 formation and ensures the prompt resolution of these structures by DDX11 to maintain processive DNA synthesis. John Wiley and Sons Inc. 2020-07-23 2020-09-15 /pmc/articles/PMC7506991/ /pubmed/32705708 http://dx.doi.org/10.15252/embj.2019104185 Text en © 2020 MRC Laboratory of Molecular Biology. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Lerner, Leticia K Holzer, Sandro Kilkenny, Mairi L Šviković, Saša Murat, Pierre Schiavone, Davide Eldridge, Cara B Bittleston, Alice Maman, Joseph D Branzei, Dana Stott, Katherine Pellegrini, Luca Sale, Julian E Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication |
title | Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication |
title_full | Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication |
title_fullStr | Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication |
title_full_unstemmed | Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication |
title_short | Timeless couples G‐quadruplex detection with processing by DDX11 helicase during DNA replication |
title_sort | timeless couples g‐quadruplex detection with processing by ddx11 helicase during dna replication |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506991/ https://www.ncbi.nlm.nih.gov/pubmed/32705708 http://dx.doi.org/10.15252/embj.2019104185 |
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