A Timeless Tale: G4 structure recognition by the fork protection complex triggers unwinding by
            <scp>DDX</scp>
            11 helicase

Freudenreich, Catherine H.

doi:10.15252/embj.2020106305

Cited by 2 publications

(2 citation statements)

References 15 publications

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“…Replication forks that encounter a G4 structure are paused. The resolution of the G4 structure is done by specific helicases that are specially recruited to the paused replication fork [15,17], including FANCJ [18][19][20], Mgs1 and Pif1 [21], and Timeless and DDX11 [22].…”

Section: Of 12mentioning

confidence: 99%

Characterization of Unidirectional Replication Forks in the Mouse Genome

Zerbib

Simon

2023

IJMS

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Origins of replication are genomic regions in which replication initiates in a bidirectional manner. Recently, a new methodology (origin-derived single-stranded DNA sequencing; ori-SSDS) was developed that allows the detection of replication initiation in a strand-specific manner. Reanalysis of the strand-specific data revealed that 18–33% of the peaks are non-symmetrical, suggesting a single direction of replication. Analysis of replication fork direction data revealed that these are origins of replication in which the replication is paused in one of the directions, probably due to the existence of a replication fork barrier. Analysis of the unidirectional origins revealed a preference of G4 quadruplexes for the blocked leading strand. Taken together, our analysis identified hundreds of genomic locations in which the replication initiates only in one direction, and suggests that G4 quadruplexes may serve as replication fork barriers in such places.

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Section: Of 12mentioning

confidence: 99%

Characterization of Unidirectional Replication Forks in the Mouse Genome

Zerbib

Simon

2023

IJMS

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“…The above reports led to a model situating the Timeless–Tipin complex between PCNA/DNA polymerase and the replicative helicase ( Gotter et al, 2007 ; Errico et al, 2009 ; Cho et al, 2013 ; Witosch et al, 2014 ). Further studies led to the identification of a DNA/G4-binding domain in human Timeless ( Freudenreich, 2020 ), postulating a new role of Timeless in the detection of obstacles/secondary structures in front of and behind the progressing fork. Timeless depletion in chicken DT40 cells resulted in a lower replication processivity and genetic instability of G4 forming sequences that could be restored by expression of human Timeless ( Lerner et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Timeless–Tipin interactions with MCM and RPA mediate DNA replication stress response

Prorok,

Wolf,

Cardoso

2024

Front. Cell Dev. Biol.

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The accuracy of replication is one of the most important mechanisms ensuring the stability of the genome. The fork protection complex prevents premature replisome stalling and/or premature disassembly upon stress. Here, we characterize the Timeless–Tipin complex, a component of the fork protection complex. We used microscopy approaches, including colocalization analysis and proximity ligation assay, to investigate the spatial localization of the complex during ongoing replication in human cells. Taking advantage of the replication stress induction and the ensuing polymerase–helicase uncoupling, we characterized the Timeless–Tipin localization within the replisome. Replication stress was induced using hydroxyurea (HU) and aphidicolin (APH). While HU depletes the substrate for DNA synthesis, APH binds directly inside the catalytic pocket of DNA polymerase and inhibits its activity. Our data revealed that the Timeless–Tipin complex, independent of the stress, remains bound on chromatin upon stress induction and progresses together with the replicative helicase. This is accompanied by the spatial dissociation of the complex from the blocked replication machinery. Additionally, after stress induction, Timeless interaction with RPA, which continuously accumulates on ssDNA, was increased. Taken together, the Timeless–Tipin complex acts as a universal guardian of the mammalian replisome in an unperturbed S-phase progression as well as during replication stress.

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A Timeless Tale: G4 structure recognition by the fork protection complex triggers unwinding by DDX 11 helicase

Cited by 2 publications

References 15 publications

Characterization of Unidirectional Replication Forks in the Mouse Genome

Characterization of Unidirectional Replication Forks in the Mouse Genome

Timeless–Tipin interactions with MCM and RPA mediate DNA replication stress response

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