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Timeless couples G‐quadruplex detection with processing by DDX 11 helicase during DNA replication

DOI: 10.15252/embj.2019104185 DOI Help

Authors: Leticia K. Lerner (MRC Laboratory of Molecular Biology) , Sandro Holzer (University of Cambridge) , Mairi Kilkenny (University of Cambridge) , Saša Šviković (MRC Laboratory of Molecular Biology) , Pierre Murat (MRC Laboratory of Molecular Biology) , Davide Schiavone (MRC Laboratory of Molecular Biology) , Cara B Eldridge (MRC Laboratory of Molecular Biology) , Alice Bittleston (University of Cambridge) , Joseph D. Maman (University of Cambridge) , Dana Branzei (IFOM, Fondazione Italiana per la Ricerca sul Cancro) , Katherine Stott (University of Cambridge) , Luca Pellegrini (University of Cambridge) , Julian E. Sale (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 14

State: Published (Approved)
Published: July 2020

Open Access Open Access

Abstract: 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 DDX 11. Loss of both Timeless and DDX 11 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 DDX 11 to maintain processive DNA synthesis.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 06/08/2020 09:28


Discipline Tags:

Life Sciences & Biotech Genetics Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)