Termination of DNA replication forks: “Breaking up is hard to do”

Bailey, Rachael; Moreno, Sara Priego; Gambus, Agnieszka

doi:10.1080/19491034.2015.1035843

Cited by 19 publications

(21 citation statements)

References 102 publications

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“…These data confirm that Topo IIα inhibition results in an accumulation of unreplicated DNA during mitosis, reflecting incomplete DNA replication in the previous S-phase. These observations are consistent with several studies in yeast or in vitro, showing that Topo IIα facilitates DNA replication [2,[27][28][29][30]. They also suggest that Topo IIα activity is essential to promote complete DNA replication in mammalian cells.…”

Section: Topoisomerase Iiα Inhibition Impairs Complete Dna Replicationsupporting

confidence: 92%

Topoisomerase IIα Prevents, But Does Not Resolve, Ultrafine Anaphase Bridges By Two Mechanisms

Gemble

Buhagiar-Labarchède

Onclercq-Delic

et al. 2019

Preprint

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Topoisomerase IIα (Topo IIα), a well-conserved double-stranded DNA (dsDNA)-specific decatenase, processes dsDNA catenanes resulting from DNA replication during mitosis. Topo IIα defects lead to an accumulation of ultrafine anaphase bridges (UFBs), a type of chromosome non-disjunction. Topo II has been reported to resolve DNA anaphase threads, possibly accounting for the increase in UFB frequency upon Topo IIinhibition. We hypothesized that the excess UFBs might also result, at least in part, from an impairment of the prevention of UFB formation by Topo II. We found that Topo IIα inhibition promotes UFB formation without affecting UFB resolution during anaphase. Moreover, we showed that Topo IIα inhibition promotes the formation of two types of UFBs depending on cell-cycle phase. Topo IIα inhibition during S-phase compromises complete DNA replication, leading to the formation of UFB-containing unreplicated DNA, whereas Topo IIα inhibition during mitosis impedes DNA decatenation at metaphase-anaphase transition, leading to the formation of UFB-containing DNA catenanes. Thus, Topo IIα activity is essential to prevent UFB formation in a cell-cycle dependent manner, but dispensable for UFB resolution during anaphase.

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Section: Topoisomerase Iiα Inhibition Impairs Complete Dna Replicationsupporting

confidence: 92%

Topoisomerase IIα Prevents, But Does Not Resolve, Ultrafine Anaphase Bridges By Two Mechanisms

Gemble

Buhagiar-Labarchède

Onclercq-Delic

et al. 2019

Preprint

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“…MCM7 is a subunit of the DNA replicative helicase in the replication complex and is involved in the initiation and elongation of replication (29, 32, 33). MCM7 helicase remains at the replication forks, even though the forks are stalled and strand breaks are induced (34, 35). γ‐H2AX colocalization with MCM7 suggests that the DSBs formed in HGPS cells are the result of the collapse of stalled replication forks.…”

Section: Resultsmentioning

confidence: 99%

Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes

et al. 2017

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the gene, resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin. This PCNA sequestration likely exposed ds-ssDNA junctions at replication forks for XPA binding. Depletion of XPA or progerin each significantly restored PCNA at replication forks. Our results suggest that although PCNA is much more competitive than XPA in binding replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding. Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, suggesting that XPA-replication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerin-induced genome instability and accelerated replicative senescence in HGPS.-Hilton, B. A., Liu, J., Cartwright, B. M., Liu, Y., Breitman, M., Wang, Y., Jones, R., Tang, H., Rusinol, A., Musich, P. R., Zou, Y. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes.

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“…During S phase, a small fraction of MCM2-7 double hexamers assemble into two active CMG helicases to fire origins promoted by CDC7 kinase and cyclin-dependent kinase (CDK) [12–16]. The rest of unused MCM2-7 double hexamers (residing at dormant origins) are likely removed by active replication forks, but it is unclear how this occurs [47,48]. At replication termination, CMG helicases are unloaded at converging forks after the final ligation step, which is regulated by polyubiquitilation of MCM7 contained within the CMG helicase, as revealed by recent studies on budding yeast and Xenopus egg extracts [49–51].…”

Section: Origin Licensing and Firingmentioning

confidence: 99%

Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

Shima

Pederson

2017

DNA Repair

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DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview of the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression. Lastly, deficiencies in the origin licensing machinery will be discussed in relation to their influence on stem cell maintenance and human diseases.

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Termination of DNA replication forks: “Breaking up is hard to do”

Cited by 19 publications

References 102 publications

Topoisomerase IIα Prevents, But Does Not Resolve, Ultrafine Anaphase Bridges By Two Mechanisms

Topoisomerase IIα Prevents, But Does Not Resolve, Ultrafine Anaphase Bridges By Two Mechanisms

Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes

Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

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