Rapid DNA replication origin licensing protects stem cell pluripotency

Matson, Jacob P.; Dumitru, Raluca; Coryell, Philip; Baxley, Ryan M.; Chen, Weili; Twaroski, Kirk; Webber, Beau R.; Tolar, Jakub; Bielinsky, Anja‐Katrin; Purvis, Jeremy E.; Cook, Jeanette Gowen

doi:10.7554/elife.30473

Cited by 90 publications

(116 citation statements)

References 82 publications

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“…Pro-self-renewing cells also had shorter cell cycle durations, on average, than both pro-mixed and pro-differentiated populations (Fig 2E). The latter finding is consistent with reports that hESC self-renewal is linked with a shortened G1 cell cycle phase (Becker et al, 2006;Matson et al, 2017).…”

Section: Selfsupporting

confidence: 93%

Inheritance of OCT 4 predetermines fate choice in human embryonic stem cells

Wolff

Kedziora

Dumitru

et al. 2018

Molecular Systems Biology

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It is well known that clonal cells can make different fate decisions, but it is unclear whether these decisions are determined during, or before, a cell's own lifetime. Here, we engineered an endogenous fluorescent reporter for the pluripotency factor OCT4 to study the timing of differentiation decisions in human embryonic stem cells. By tracking single‐cell OCT4 levels over multiple cell cycle generations, we found that the decision to differentiate is largely determined before the differentiation stimulus is presented and can be predicted by a cell's preexisting OCT4 signaling patterns. We further quantified how maternal OCT4 levels were transmitted to, and distributed between, daughter cells. As mother cells underwent division, newly established OCT4 levels in daughter cells rapidly became more predictive of final OCT4 expression status. These results imply that the choice between developmental cell fates can be largely predetermined at the time of cell birth through inheritance of a pluripotency factor.

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Section: Selfsupporting

confidence: 93%

Inheritance of OCT 4 predetermines fate choice in human embryonic stem cells

Wolff

Kedziora

Dumitru

et al. 2018

Molecular Systems Biology

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“…RPE cell cycle kinetics were better fitted with higher rates through more numerous steps, followed by U2OS, then by H9 with slower rates and fewer steps. The one exception to this pattern was G1 in H9 ( Fig 2D and F), which is consistent with the unusually short G1 duration in embryonic stem cells (White & Dalton, 2005;Becker et al, 2006;Matson et al, 2017). Although this analysis makes no claims about the actual molecular mechanisms that control phase durations, it further supports the hypothesis that each cell cycle phase obeys a unique rate-governing process and is therefore consistent with the observation that phase durations are uncorrelated.…”

Section: Each Cell Cycle Phase Follows An Erlang Distribution With a supporting

confidence: 84%

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

Chao

Fakhreddin

Shimerov

et al. 2019

Molecular Systems Biology

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The cell cycle is canonically described as a series of four consecutive phases: G1, S, G2, and M. In single cells, the duration of each phase varies, but the quantitative laws that govern phase durations are not well understood. Using time‐lapse microscopy, we found that each phase duration follows an Erlang distribution and is statistically independent from other phases. We challenged this observation by perturbing phase durations through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Despite large changes in durations in cell populations, phase durations remained uncoupled in individual cells. These results suggested that the independence of phase durations may arise from a large number of molecular factors that each exerts a minor influence on the rate of cell cycle progression. We tested this model by experimentally forcing phase coupling through inhibition of cyclin‐dependent kinase 2 ( CDK 2) or overexpression of cyclin D. Our work provides an explanation for the historical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states.

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“…The analysis revealed no observable change in the number or intensity of EdU positive cells with STN1 depletion compared to controls, suggesting DNA synthesis is not significantly affected with STN1 depletion, as previously reported ( Figure 2B) (Wang et al, 2014. Likewise, when we compared chromatin-bound MCM across the cell cycle, we found the expected increase in MCM positive cells in G1 (origin licensing) followed by a linear decrease throughout S-phase (origin firing/DNA synthesis) with very few MCM6 positive cells in G2/M ( Figure 2B) (Matson, Dumitru et al, 2017). However, the G1 population of shSTN1 cells exhibited an increase in MCM6 intensity compared to the control cells in mean intensity of MCM6 positive cells, suggesting increased origin licensing after STN1 depletion ( Figure 2C-E).…”

Section: Stn1 Depletion Leads To Increased MCM In G1 and S-phasesupporting

confidence: 87%

Human CST suppresses origin licensing and promotes AND-1/Ctf4 chromatin association

Wang

Brady

Caiello

et al. 2019

Preprint

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Human CTC1-STN1-TEN1 (CST) is an RPA-like single-stranded DNA binding protein that interacts with DNA polymerase a-primase (pol a) and functions in telomere replication. Previous studies suggest that CST also promotes replication restart following fork stalling. However, the precise role of CST in genome-wide replication remains unclear. In this study, we sought to understand whether CST alters origin licensing and activation. Replication origins are licensed by loading of the minichromosome maintenance 2-7 (MCM) complex in G1 followed by replisome assembly and origin firing in S-phase. We find that CST directly interacts with the MCM complex and disrupts binding of CDT1 to MCM, leading to decreased origin licensing. We also show that CST enhances replisome assembly by promoting AND-1/pol a chromatin association. Moreover, these interactions are not dependent on exogenous replication stress, suggesting that CST acts as a specialized replication factor during normal replication. Overall, our findings implicate CST as a novel regulator of origin licensing and replisome assembly/fork progression through interactions with MCM, AND-1 and pol a.

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Rapid DNA replication origin licensing protects stem cell pluripotency

Cited by 90 publications

References 82 publications

Inheritance of OCT 4 predetermines fate choice in human embryonic stem cells

Inheritance of OCT 4 predetermines fate choice in human embryonic stem cells

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

Human CST suppresses origin licensing and promotes AND-1/Ctf4 chromatin association

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