Origin of DNA replication at the human lamin B2 locus: OBR or ABR?

Lee, Hoyun; Romero, Julia

doi:10.4161/cc.21992

Cited by 7 publications

(16 citation statements)

References 12 publications

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“…43 For cells arrested at the G1/S border, Smc1 was strongly associated with both replication zones I and II (Prom4, HS(A)), the flanking region (CodR5), and upstream putative enhancer region represented by AT-2 primer. 39,40 Smc3 also showed strong association with origin and the flanking region at 0 h post-G1/S. By 1 h post-G1/S, both Smc1 and Smc3 were dissociated from replication zone I, although Smc1 still showed strong association with replication zone II ( Fig.…”

Section: Cohesin and Mediator Flank The Dbf4 Promoter Region In A Celmentioning

confidence: 88%

“…2 in the cited reference). 39,40 Quantification data for mRNA abundance for 2 independent experiments were plotted against Dbf4 origin activity to show relative abundance of transcript versus replication activity. (C) Northern blotting of Dbf4 mRNA isolated from HeLa S3 cells synchronized at G1/S-and-released is shown.…”

Section: Dbf4 Transcription Is Downregulated When Origin Activity Is mentioning

confidence: 99%

“…S1). [39][40][41] In the current study, we used the human Dbf4 origin-promoter model to examine the mechanism how transcription and DNA replication are co-regulated. We found that gene transcription activity at the Dbf4 locus was quite dramatically down-regulated during origin firing.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic regulation of histone H3K9 is linked to the switch between replication and transcription at the Dbf4 origin-promoter locus

et al. 2016

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The co-regulation of DNA replication and gene transcription is still poorly understood. To gain a better understanding of this important control mechanism, we examined the DNA replication and transcription using the Dbf4 origin-promoter and Dbf4 pseudogene models. We found that origin firing and Dbf4 transcription activity were inversely regulated in a cell cycle-dependent manner. We also found that proteins critical for the regulation of replication (ORC, MCM), transcription (SP1, TFIIB), and cohesin (Smc1, Smc3) and Mediator functions (Med1, Med12) interact with specific sites within and the surrounding regions of the Dbf4 locus in a cell cycle-dependent manner. As expected, replication initiation occurred within a nucleosome-depleted region, and nucleosomes flanked the 2 replication initiation zones. Further, the histone H3 in this region was distinctly acetylated or trimethylated on lysine 9 in a cell cycledependent fluctuation pattern: H3K9ac was most prevalent when the Dbf4 transcription level was highest whereas the H3K9me3 level was greatest during and just after replication. The KDM4A histone demethylase, which is responsible for the H3K9me3 modification, was enriched at the Dbf4 origin in a manner coinciding with H3K9me3. Finally, HP1g, a protein known to interact with H3K9me3 in the heterochromatin was also found enriched at the origin during DNA replication, indicating that H3K9me3 may be required for the regulation of replication at both heterochromatin and euchromatin regions. Taken together, our data show that mammalian cells employ an extremely sophisticated and multilayered co-regulation mechanism for replication and transcription in a highly coordinated manner.

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Section: Cohesin and Mediator Flank The Dbf4 Promoter Region In A Celmentioning

confidence: 88%

Section: Dbf4 Transcription Is Downregulated When Origin Activity Is mentioning

confidence: 99%

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Dynamic regulation of histone H3K9 is linked to the switch between replication and transcription at the Dbf4 origin-promoter locus

et al. 2016

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“…We next determined the binding abilities of different phospho-Cdc7 alleles using origins at the DBF4 and MCM4 loci. [35][36][37] As shown in Fig. 2D, phospho-dead Cdc7 allele (Cdc7 £5A ) showed the highest affinity for both the MCM4 and DBF4 origins.…”

Section: Cdk-dependent Phosphorylation Regulates Cdc7 Interaction Witmentioning

confidence: 99%

“…Data from a chromatin immunoprecipitation (ChIP) assay using the well-characterized Dbf4 origin in HEK293T cells 35,36 showed that Cdc7 was not enriched at the DBF4 origin until 6 h post-NZ ( Fig. 2B and C) the time when cells are the new cell cycle.…”

Section: Cdk-dependent Phosphorylation Regulates Cdc7 Interaction Witmentioning

confidence: 99%

Cdk1-mediated phosphorylation of Cdc7 suppresses DNA re-replication

et al. 2016

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To maintain genetic stability, the entire mammalian genome must replicate only once per cell cycle. This is largely achieved by strictly regulating the stepwise formation of the pre-replication complex (pre-RC), followed by the activation of individual origins of DNA replication by Cdc7/Dbf4 kinase. However, the mechanism how Cdc7 itself is regulated in the context of cell cycle progression is poorly understood. Here we report that Cdc7 is phosphorylated by a Cdk1-dependent manner during prometaphase on multiple sites, resulting in its dissociation from origins. In contrast, Dbf4 is not removed from origins in prometaphase, nor is it degraded as cells exit mitosis. Our data thus demonstrates that constitutive phosphorylation of Cdc7 at Cdk1 recognition sites, but not the regulation of Dbf4, prevents the initiation of DNA replication in normally cycling cells and under conditions that promote re-replication in G2/M. As cells exit mitosis, PP1a associates with and dephosphorylates Cdc7. Together, our data support a model where Cdc7 (de)phosphorylation is the molecular switch for the activation and inactivation of DNA replication in mitosis, directly connecting Cdc7 and PP1a/Cdk1 to the regulation of once-per-cell cycle DNA replication in mammalian cells.

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