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Timeless couples G‐quadruplex detection with processing by DDX 11 helicase during DNA replication
Author(s) -
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
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019104185
Subject(s) - library science , computer science
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.