scholarly journals Electrical induction hypothesis to explain enhancer-promoter communication

2015 ◽  
Author(s):  
Valentina Agoni
Keyword(s):  
Transcription Factors ◽  
Dna Replication ◽  
Induction Hypothesis ◽  
Unsolved Problem ◽  
Specific Binding ◽  
Replication Machinery ◽  
Replication Process ◽  
Electrical Induction ◽  
Binding Sequence

The steps of the DNA replication process remains to be clarified. Transcription factors are supposed to find their specific binding-sequence driven by epigenetic modifications and GpC islands. But then how can the replication machinery be able to find the promoters of exactly the genes that the cell needs to transcribe in that moment? Here we hypothesize a role of DNA conductance and electrical induction to give an explanation to this unsolved problem. Our hypothesis goes in accordance with the fact that many authors identified 3D loops in the genomes.

scholarly journals Electrical induction hypothesis to explain enhancer-promoter communication

2015 ◽  
Author(s):  
Valentina Agoni
Keyword(s):  
Transcription Factors ◽  
Dna Replication ◽  
Induction Hypothesis ◽  
Unsolved Problem ◽  
Specific Binding ◽  
Replication Machinery ◽  
Replication Process ◽  
Electrical Induction ◽  
Binding Sequence

The steps of the DNA replication process remains to be clarified. Transcription factors are supposed to find their specific binding-sequence driven by epigenetic modifications and GpC islands. But then how can the replication machinery be able to find the promoters of exactly the genes that the cell needs to transcribe in that moment? Here we hypothesize a role of DNA conductance and electrical induction to give an explanation to this unsolved problem. Our hypothesis goes in accordance with the fact that many authors identified 3D loops in the genomes.

scholarly journals LMO2 Regulates DNA Replication in Hematopoietic Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 553-553
Author(s):  
Marie-Claude Sincennes ◽  
Magali Humbert ◽  
Benoit Grondin ◽  
Christophe Cazaux ◽  
Veronique Lisi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Dna Replication ◽  
Cell Fate ◽  
Binding Sites ◽  
Erythroid Differentiation ◽  
S Phase

Abstract Oncogenic transcription factors are major drivers in acute leukemias. These oncogenes are believed to subvert normal cell identity via the establishment of gene expression programs that dictate cell differentiation and growth. The LMO2 oncogene, which is commonly activated in T-cell acute lymphoblastic leukemia (T-ALL), has a well-established function in transcription regulation. We and others previously demonstrated that LMO1 or LMO2 collaborate with the SCL transcription factor to activate a self-renewal program that converts non self-renewing progenitors into pre-leukemic stem cells. Here we demonstrate a non-transcriptional role of LMO2 in controlling cell fate by directly promoting DNA replication, a hitherto unrecognized mechanism that might also account for its oncogenic properties. To address the question whether LMO2 controls other functions via protein-protein interactions, we performed a proteome-wide screen for LMO2 interaction partners in Kit+ Lin- cells. In addition to known LMO2-interacting proteins such as LDB1 and to proteins associated with transcription, we unexpectedly identified new interactions with three essential DNA replication enzymes, namely minichromosome 6 (MCM6), DNA polymerase delta (POLD1) and DNA primase (PRIM1). First, we show that in Kit+ hematopoietic cells (TF-1), all components of the pre-replication complex co-immunoprecipitate with LMO2 but not with SCL, suggesting a novel SCL-independent function. Second, LMO2 is recruited to DNA replication origins in these cells together with MCM5. Third, tethering LMO2 to synthetic DNA sequences is sufficient to transform these into origins of replication. Indeed, we show by DNA capture that LMO2 fused to the DNA binding domain of GAL4 is sufficient to recruit DNA replication proteins to GAL4 binding sites on DNA. In vivo, this recruitment is sufficient to drive DNA replication in a manner which is dependent on the integrity of the GAL4 binding sites. These results provide unambiguous evidence for a role of LMO2 in directly controlling DNA replication. Cell cycle and cell differentiation are tightly coordinated during normal hematopoiesis, both during erythroid differentiation and during thymocyte development. We next addressed the functional importance of LMO2 in these two lineages. Erythroid cell differentiation proceeds through different stages from the CD71+Ter119- to the CD71-Ter119+. These stages are also distinguishable by morphological criteria. We observe that LMO2 protein levels directly correlate with the proportion of cells in S phase, i.e. both LMO2 levels and the proportions of cycling cells decrease with terminal erythroid differentiation. Strikingly, lowering LMO2 levels in fetal liver erythroid progenitors via shRNAs decreases the proportion of cells in S phase and arrests Epo-dependent cell growth. Despite a drastic decrease in the numbers of erythroid precursors, these cells differentiate readily to the CD71-Ter119+ stage. Therefore, LMO2 levels dictate cell fate in the erythroid lineage, by favoring DNA replication at the expense of terminal maturation. Conversely, ectopic expression in thymocytes induces DNA replication and drives cells into cell cycle, causing differentiation blockade. Our results define a novel role for the oncogenic transcription factor LMO2 in directly promoting DNA synthesis. To our knowledge, this is the first evidence for a non-transcriptional function of the LMO2 oncogene that drives cell cycle at the expense of differentiation, favouring progenitor cell expansion in the thymus, and causing T-ALL when ectopically expressed in the T lineage. We propose that the non-transcriptional control of DNA replication uncovered here for LMO2 may be a more common function of oncogenic transcription factors than previously appreciated. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interplay of host regulatory network on SARS-CoV-2 binding and replication machinery

2020 ◽  
Author(s):  
Shiek SSJ Ahmed ◽  
Prabu Paramasivam ◽  
Kamal Raj ◽  
Vishal Kumar ◽  
Ram murugesan ◽  
...  
Keyword(s):  
Viral Replication ◽  
Intermediate Phase ◽  
Receptor Activation ◽  
Host Protein ◽  
Replication Machinery ◽  
Replication Process ◽  
Infection Pattern ◽  
Protein Interactome ◽  
Signaling Process

AbstractWe dissect the mechanism of SARS-CoV-2 in human lung host from the initial phase of receptor binding to viral replication machinery. We constructed two independent lung protein interactome to reveal the signaling process on receptor activation and host protein hijacking machinery in the pathogenesis of virus. Further, we test the functional role of the hubs derived from both interactome. Most hubs proteins were differentially regulated on SARS-CoV-2 infection. Also, the proteins of viral replication hubs were related with cardiovascular disease, diabetes and hypertension confirming the vulnerability and severity of infection in the risk individual. Additionally, the hub proteins were closely linked with other viral infection, including MERS and HCoVs which suggest similar infection pattern in SARS-CoV-2. We identified five interconnecting cascades between hubs of both networks that show the preparation of optimal environment in the host for viral replication process upon receptor attachment. Interestingly, we propose that seven potential miRNAs, targeting the intermediate phase that connects receptor and viral replication process a better choice as a drug for SARS-CoV-2.

scholarly journals An analysis of the regulation of DNA synthesis by cdk2, Cip1, and licensing factor.

1995 ◽  
Vol 129 (1) ◽  
pp. 1-15 ◽  
Author(s):  
H Yan ◽  
J Newport
Keyword(s):  
Dna Replication ◽  
Kinase Inhibitor ◽  
Negative Regulator ◽  
Sperm Chromatin ◽  
Early Event ◽  
Replication Process ◽  
P21 Protein ◽  
Licensing Factor ◽  
Additional Support

The activation of DNA replication appears to involve at least four steps. These include origin recognition, origin unwinding, primer synthesis, and a switching step to a continuous elongation mode. Moreover, in higher eukaryotes a number of studies have shown that much of the DNA replication which occurs is restricted to specific sites within the nuclei. It has been proposed that these replication foci are composed of a large number of origin sites which are clustered together into an aggregate. The molecular basis for this aggregation is currently not well understood. Regulation of the activation of DNA replication is a complicated process. The G1-S kinase cdk2 is a positive regulator of replication. The p21 protein is a negative regulator of replication both by inhibiting cdk2 kinase and the replication protein PCNA. Moreover, it has been proposed that origin usage is restricted to a single firing per cell cycle by a "licensing factor." Using a cell-free replication system derived from Xenopus eggs we have investigated at what step in the replication process these regulators participate. We present evidence that the clustered organization of DNA into foci is not a transient arrangement, but rather, it persists following DNA replication. We also find that foci form on both sperm chromatin and bacteriophage lambda DNA incubated in extracts depleted of cdk2 kinase. Therefore, our data support the conclusion that organization of chromatin into foci is an early event in the replication pathway preceding activation of cdk2 kinase. With respect to the role of cdk2 during activation of DNA replication we find that in cdk2-depleted extracts primer synthesis does not occur and RP-A remains tightly associated with foci. This strongly suggests that cdk2 kinase is required for activating the origin unwinding step of the replication process. Consistent with this interpretation we find that addition of rate limiting quantities of the cdk2 inhibitor p21 protein to an extract delays primer synthesis. Interestingly, in the presence of p21 primer synthesis does occur after a delay and then replication arrests. This is consistent with the published demonstration that p21 can inhibit PCNA, a protein required for replication beyond the priming step. Therefore, our results provide additional support to the proposal that the post-priming switching step is a key regulatory step in replication. With respect to the role of licensing factor during DNA replication it has recently been shown that treatment of mitotic extracts with kinase inhibitor DMAP inactivates "licensing factor."(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Heterochromatin Replication: Direct Interaction of DNA replication machinery with heterochromatin code writer Clr4/Suv39 and reader Swi6/HP1 in S. pombe

2020 ◽  
Author(s):  
Sharanjot Saini ◽  
Sumit Arora ◽  
Kamlesh K. Bisht ◽  
Nandni Nakwal ◽  
Shakil Ahmed ◽  
...  
Keyword(s):  
Dna Replication ◽  
Mating Type ◽  
Central Element ◽  
Direct Interaction ◽  
Epigenetic Mark ◽  
Replication Machinery ◽  
Multiple Cell ◽  
Heterochromatin Assembly ◽  
Mitosis And Meiosis

The establishment of heterochromatin in fission yeast involves methyltransferase Clr4-mediated H3-Lys9 methylation, which is bound specifically by Swi6/HP1. However, the mechanism of propagation of heterochromatin through multiple cell divisions is not known. A role of DNA replication in propagating the heterochromatin is envisaged. Studies in S. pombe have indicated a direct interaction between DNA Polα and Swi6/HP1 and between DNA Polε and Rik1-Dos2 complex, suggesting a coupling between DNA replication and heterochromatin assembly. Here, we show that like DNA Polα, Polδ, which plays a role in both leading and lagging strand replication, also plays a role in silencing at mating type and centromere. We show that both the polymerases α and δ interact directly with both Clr4 and Swi6/HP1. Mutations in both the polymerases lead to decrease in H3-Lys9 methylation and Swi6 at the mating type and left outer repeats of centromeres I and II, with a reciprocal increase in their level at the central element, cnt, at all the three centromeres. These mutations also cause defects in chromosome segregation, recruitment of Cohesin and chromosome dynamics during mitosis and meiosis. Thus, our results indicate that a tight coordination between DNA replication machinery and propagation of the heterochromatin-specific epigenetic mark.

The Role of Transcription Factors in Adenovirus DNA Replication

1992 ◽  
pp. 331-346
Author(s):  
P. C. van der Vliet ◽  
C. P. Verrijzer ◽  
Y. M. Mul ◽  
J. A. W. M. van Oosterhout ◽  
W. van Driel
Keyword(s):  
Transcription Factors ◽  
Dna Replication

scholarly journals Mitochondrial DNA replication in mammalian cells: overview of the pathway

2018 ◽  
Vol 62 (3) ◽  
pp. 287-296 ◽  
Author(s):  
Maria Falkenberg
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Mitochondrial Diseases ◽  
Replication Machinery ◽  
Replication Process ◽  
Double Stranded Dna ◽  
Mammalian Mitochondria ◽  
Multiple Copies ◽  
Mitochondrial Replication ◽  
Replication Factors

Mammalian mitochondria contain multiple copies of a circular, double-stranded DNA genome and a dedicated DNA replication machinery is required for its maintenance. Many disease-causing mutations affect mitochondrial replication factors and a detailed understanding of the replication process may help to explain the pathogenic mechanisms underlying a number of mitochondrial diseases. We here give a brief overview of DNA replication in mammalian mitochondria, describing our current understanding of this process and some unanswered questions remaining.

The role of Forkhead Box O 3a (FoxO3a) Transcription Factors in the Pathogenesis of Pulmonary Fibrosis

Pneumologie ◽  
2012 ◽  
Vol 66 (06) ◽  
Author(s):  
HM Al-Tamari ◽  
M Eschenhagen ◽  
A Schmall ◽  
R Savai ◽  
HA Ghofrani ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Pulmonary Fibrosis ◽  
Forkhead Box
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