Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
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
_version_ 1783585139856506880
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
work_keys_str_mv AT lernerleticiak timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT holzersandro timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT kilkennymairil timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT svikovicsasa timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT muratpierre timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT schiavonedavide timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT eldridgecarab timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT bittlestonalice timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT mamanjosephd timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT branzeidana timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT stottkatherine timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT pellegriniluca timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication
AT salejuliane timelesscouplesgquadruplexdetectionwithprocessingbyddx11helicaseduringdnareplication