Metazoan DNA replication origins

Ganier, Olivier; Prorok, Paulina; Akerman, İldem; Méchali, Marcel

doi:10.1016/j.ceb.2019.03.003

Cited by 51 publications

(39 citation statements)

References 98 publications

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“…DNA replication origin specification remains poorly understood despite the progress in next-generation sequencing technology that allowed IS mapping genome-wide. In this study, we used the SNS-Seq method, which has the highest resolution to map replication origins 1 , in which the signal was corrected with suitable experimental controls generated in parallel (see Methods section). We found a remarkable consistency in the specification of a subset of IS, termed core origins, in multiple cell types that is maintained even after immortalisation.…”

Section: Discussionmentioning

confidence: 99%

“…The positioning of DNA replication initiation sites (IS) in the genome (origin specification) is poorly understood in metazoans. In prokaryotes and viruses, usually a single, sequencespecific origin exists, while in the eukaryote Saccharomyces cerevisiae, DNA replication initiates from AT-rich consensus sequences that are bound by the yeast origin recognition complex (ORC) 1 . By contrast, in fruit fly and mouse cells, the presence of a G-rich DNA sequence element, (Origin G-rich Repeated Element, OGRE), 300 bp upstream of the IS has been reported in more than 60% of origins [2][3][4][5][6][7] .…”

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A predictable conserved DNA base composition signature defines human core DNA replication origins

et al. 2020

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DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.

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Section: Discussionmentioning

confidence: 99%

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A predictable conserved DNA base composition signature defines human core DNA replication origins

et al. 2020

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“…DNA replication initiation is a two-step process. In G1 phase, origins are licensed by the loading of MCM2-7 complexes, while in S phase, a fraction of the origins are activated by the CDK and DDK dependent recruitment of CDC45, the GINS complex, and the rest of replisome (Ganier et al, 2019;Marchal et al, 2019). To identify at which stage of replication initiation FAM111A may function, we first examined the origin licensing efficiency in FAM111A depleted cells by quantifying MCM2 abundance on chromatin in G1 phase cells by high throughput microscopy (HTM) ( Fig.…”

Section: Fam111a Promotes Origin Activation At the G1/s Transitionmentioning

confidence: 99%

FAM111A regulates replication origin activation and cell fitness

Rios-Szwed

Garcia-Wilson

Sánchez‐Pulido

et al. 2020

Preprint

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FAM111A is a replisome associated protein and dominant mutations within its trypsinlike peptidase domain are linked to severe human developmental syndromes. However, FAM111A functions and its putative substrates remain largely unknown. Here, we showed that FAM111A promotes origin activation and interacts with the putative peptidase FAM111B, and we identified the first potential FAM111A substrate, the suicide enzyme HMCES. Moreover, unrestrained expression of FAM111A wild-type and patient mutants impaired DNA replication and caused cell death only when the peptidase domain remained intact. Altogether our data reveal how FAM111A promotes DNA replication in normal conditions and becomes harmful in a disease context.

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“…While origins have been successfully mapped in other eukaryotes, their locations are not easily predicted from DNA sequences. Highly active replication origins in several vertebrates have recently been shown to have some common general features such as open chromatin, GC‐rich sequences, G4 quadruplex structures, or proximity to active genes (reviewed in ).…”

Section: G1: Preparing Dna For S Phasementioning

confidence: 99%

Preparation for DNA replication: the key to a successful S phase

Limas

Cook

2019

FEBS Letters

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Successful genome duplication is required for cell proliferation and demands extraordinary precision and accuracy. The mechanisms by which cells enter, progress through, and exit S phase are intense areas of focus in the cell cycle and genome stability fields. Key molecular events in the G1 phase of the cell division cycle, especially origin licensing, are essential for pre‐establishing conditions for efficient DNA replication during the subsequent S phase. If G1 events are poorly regulated or disordered, then DNA replication can be compromised leading to genome instability, a hallmark of tumorigenesis. Upon entry into S phase, coordinated origin firing and replication progression ensure complete, timely, and precise chromosome replication. Both G1 and S phase progressions are controlled by master cell cycle protein kinases and ubiquitin ligases that govern the activity and abundance of DNA replication factors. In this short review, we describe current understanding and recent developments related to G1 progression and S phase entrance and exit with a particular focus on origin licensing regulation in vertebrates.

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Metazoan DNA replication origins

Cited by 51 publications

References 98 publications

A predictable conserved DNA base composition signature defines human core DNA replication origins

A predictable conserved DNA base composition signature defines human core DNA replication origins

FAM111A regulates replication origin activation and cell fitness

Preparation for DNA replication: the key to a successful S phase

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