Mechanisms regulating S phase progression in mammalian cells

Maya-Mendoza, Apolinar; Tang, Chi W.; Pombo, Ana; Jackson, Dean A.

doi:10.2741/3523

Cited by 13 publications

(12 citation statements)

References 60 publications

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“…Whsc1 -deficient cells have large deregulations of gene sets involved in key biological processes, among them the genes involved in DNA repair and DNA replication. They also present a significantly decreased fork rate counteracted by local increases in origin density suggesting that a higher frequency of stalled forks induces compensatory activation of dormant origins and triggers a DNA damage response (Maya-Mendoza et al, 2009). The fact that the Fanconi Anemia (FA) pathway (responsible for repairing DNA as a response of replication stress (Kais et al, 2016)) is significantly altered further supports this idea.…”

Section: Discussionmentioning

confidence: 99%

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

et al. 2017

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SUMMARY Immunodeficiency is one of the most important causes of mortality associated to Wolf-Hirschhorn Syndrome (WHS), a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1) gene has been proposed as one of the main responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness and proliferation, therefore demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients.

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Section: Discussionmentioning

confidence: 99%

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

et al. 2017

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“…Replication in each consecutive S phase is initiated in the same areas, but the selection of specific initiation positions in these defined areas is random and never exactly the same (11). The switch in the initiation pattern to the less frequent has been suggested to happen due to changes in chromatin structure (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian replication initiation in its essence is a fairly random process (11). The origin recognition complex (ORC) does not have a consensus recognition site and would initiate replication of any kind of DNA fragment in vitro (12), while its binding is limited to specific areas in vivo (13).…”

Section: Introductionmentioning

confidence: 99%

A distinct first replication cycle of DNA introduced in mammalian cells

Chandok

Kapoor

Brick

et al. 2010

Nucleic Acids Research

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Many mutation events in microsatellite DNA sequences were traced to the first embryonic divisions. It was not known what makes the first replication cycles of embryonic DNA different from subsequent replication cycles. Here we demonstrate that an unusual replication mode is involved in the first cycle of replication of DNA introduced in mammalian cells. This alternative replication starts at random positions, and occurs before the chromatin is fully assembled. It is detected in various cell lines and primary cells. The presence of single-stranded regions increases the efficiency of this alternative replication mode. The alternative replication cannot progress through the A/T-rich FRA16B fragile site, while the regular replication mode is not affected by it. A/T-rich microsatellites are associated with the majority of chromosomal breakpoints in cancer. We suggest that the alternative replication mode may be initiated at the regions with immature chromatin structure in embryonic and cancer cells resulting in increased genomic instability. This work demonstrates, for the first time, differences in the replication progression during the first and subsequent replication cycles in mammalian cells.

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“…Labelled DNA fibres can then be used to develop detailed information about fork rates and the distribution of active replicons and how individual replicons are activated in different cell cycles (Jackson and Pombo 1998;Takebayashi et al 2001). Most importantly, DNA fibres prepared from cells that were labelled with different replication precursor analogues during consecutive cell cycles provided compelling evidence that structurally stable replicon clusters generate DNA foci that represent both structural and functional sub-chromosomal units (reviewed in Maya-Mendoza et al 2009). …”

Section: Single Molecule Analysis On Dna Fibresmentioning

confidence: 99%

S-phase progression in mammalian cells: modelling the influence of nuclear organization

et al. 2010

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The control of DNA replication is of fundamental importance as cell proliferation demands that identical copies of the genetic material are passed to the two daughter cells that form during mitosis. These genetic copies are generated in the preceding S phase, where the entire DNA complement of the mother cell must be copied exactly once. As part of this process, it is known that different regions of mammalian genomes are replicated at specific times of a temporally defined replication programme. The key feature of this programme is that active genes in euchromatin are replicated before inactive ones in heterochromatin. This separation of S phase into periods where different classes of chromatin are duplicated is important in maintaining changes in gene expression that define individual cell types. Recent attempts to understand the structure of the S-phase timing programme have focused on the use of genome-wide strategies that inevitably use DNA isolated from large cell populations for analysis. However, this approach provides a composite view of events that occur within a population without knowledge of the cell-to-cell variability across the population. In this review, we attempt to combine information generated using genome-wide and single cell strategies in order to develop a coherent molecular understanding of S-phase progression. During this integration, we have explored how available information can be introduced into a modelling environment that best describes S-phase progression in mammalian cells.

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Mechanisms regulating S phase progression in mammalian cells

Cited by 13 publications

References 60 publications

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

A distinct first replication cycle of DNA introduced in mammalian cells

S-phase progression in mammalian cells: modelling the influence of nuclear organization

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