Can Artificially Designed Protein Combat Cancer?

For a long time, cancer-therapeutic drugs are made to targetvarious DDR components present especially in cancerous cells [7].But let’s think the other way round can we utilize the high frequency of Replication-Transcription collision in cancerous cells and design a certain protein that can identify the collision sites and bindto and fuse both Transcription-Replication types of machinery, toirreversibly cause Replication Fork Stalling, the precancerous andcancerous cells will eventually get degraded as their genome willnot replicate. The question here is If a protein can be devised, ableto detect the collision sites and fuse the two types of machineryirreversibly, can division and metastasis of pre-/cancerous be prevented?At the onset of collision, the cell synthesizes Fob1 protein tobind to the DNA sequence, present in between the soon-to-collideReplication-Transcription machinery, known as Replication ForkBarrier (RFB) site, to prevent a collision [8]. The Fob1 protein’sgene sequence can be procured and can be used to incorporate ourdesigner protein sequence in place of the Fob1 gene, using Group 2Intron mediated gene replacement. so that whenever the cell generates the Fob1 synthesis signal, our Protein-X will be synthesizedin place of Fob1. Using Bioinformatics tools, Protein-X should bedesigned in such a way, that it must have 2 specific domains to bindto the RNA polymerase and the DNA polymerases (like NtrC and other transcriptional factors), and form a bridge-like bond in between them, that is permanent. By this, the two colliding machineries will fuse, causing multiple irreversible fork stalls throughoutthe genome at the collision sites, ultimately causing failure in genome duplication. And thereby, cancer-prone cells will eventuallydegrade

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Faculty Opinions recommendation of Evidence from mutational specificity studies that yeast DNA polymerases delta and epsilon replicate different DNA strands at an intracellular replication fork.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1116665.572729 ◽

2008 ◽

Author(s):

Kevin Sweder

Keyword(s):

Replication Fork ◽

Dna Polymerases ◽

Intracellular Replication ◽

Mutational Specificity ◽

Dna Strands

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Comparison of wavelet continuous transform and signal averaged ECG for high frequency content and late potential detection in healthy individuals

European Heart Journal ◽

10.1093/ehjci/ehaa946.3447 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

D Garcia Iglesias ◽

J.M Rubin Lopez ◽

D Perez Diez ◽

C Moris De La Tassa ◽

F.J De Cos Juez ◽

...

Keyword(s):

High Frequency ◽

Classical Method ◽

Total Power ◽

Frequency Content ◽

Healthy Individuals ◽

Time Frequency ◽

Qt Intervals ◽

Long Time ◽

Power Content ◽

High Frequency Content

Abstract Introduction The Signal Averaged ECG (SAECG) is a classical method forSudden Cardiac Death (SCD) risk assessment, by means of Late Potentials (LP) in the filtered QRS (fQRS)[1]. But it is highly dependent on noise and require long time records, which make it tedious to use. Wavelet Continuous Transform (WCT) meanwhile is easier to use, and may let us to measure the High Frequency Content (HFC) of the QRS and QT intervals, which also correlates with the risk of SCD [2,3]. Whether the HFC of the QRS and QT measured with the WCT is a possible subrogate of LP, has never been demonstrated. Objective To demonstrate if there is any relationship between the HFC measured with the WCT and the LP analyzed with the SAECG. Methods Data from 50 consecutive healthy individuals. The standard ECG was digitally collected for 3 consecutive minutes. For the WCT Analysis 8 consecutive QT complexes were used and for the SAECG Analysis all available QRS were used. The time-frequency data of each QT complex were collected using the WCT as previously described [3] and the Total, QRS and QT power were obtained from each patient. For the SAECG, bipolar X, Y and Z leads were used with a bidirectional filter at 40 to 250 Hz [1]. LP were defined as less than 0.05 z in the terminal part of the filtered QRS and the duration (SAECG LP duration) and root mean square (SAECG LP Content) of this LP were calculated. Pearson's test was used to correlate the Power content with WCT analysis and the LP in the SAECG. Results There is a strong correlation between Total Power and the SAECG LP content (r=0.621, p<0.001). Both ST Power (r=0.567, p<0.001) and QRS Power (r=0.404, p=0.004) are related with the SAECG LP content. No correlation were found between the Power content (Total, QRS or ST Power) and the SAECG LP duration. Also no correlation was found between de SAECG LP content and duration. Conclusions Total, QRS and ST Power measured with the WCT are good surrogates of SAECG LP content. No correlation were found between WCT analysis and the SAECG LP duration. Also no correlation was found between the SAECG LP content and duration. This can be of high interest, since WCT is an easier technique, not needing long recordings and being less affected by noise. Funding Acknowledgement Type of funding source: None

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Probiotics: A Promising Candidate for Management of Colorectal Cancer

Cancers ◽

10.3390/cancers13133178 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3178

Author(s):

Ashutosh Tripathy ◽

Jayalaxmi Dash ◽

Sudhakar Kancharla ◽

Prachetha Kolli ◽

Deviyani Mahajan ◽

...

Keyword(s):

Colorectal Cancer ◽

Treatment Strategies ◽

Intestinal Barrier ◽

World Health ◽

Intestinal Barrier Function ◽

Cancer Type ◽

Prevention Therapy ◽

Long Time ◽

Health Organization ◽

Cancerous Cells

Colorectal cancer (CRC) is the World’s third most frequently diagnosed cancer type. It accounted for about 9.4% mortality out of the total incidences of cancer in the year 2020. According to estimated facts by World Health Organization (WHO), by 2030, 27 million new CRC cases, 17 million deaths, and around 75 million people living with the disease will appear. The facts and evidence that establish a link between the intestinal microflora and the occurrence of CRC are quite intuitive. Current shortcomings of chemo- and radiotherapies and the unavailability of appropriate treatment strategies for CRC are becoming the driving force to search for an alternative approach for the prevention, therapy, and management of CRC. Probiotics have been used for a long time due to their beneficial health effects, and now, it has become a popular candidate for the preventive and therapeutic treatment of CRC. The probiotics adopt different strategies such as the improvement of the intestinal barrier function, balancing of natural gut microflora, secretion of anticancer compounds, and degradation of carcinogenic compounds, which are useful in the prophylactic treatment of CRC. The pro-apoptotic ability of probiotics against cancerous cells makes them a potential therapeutic candidate against cancer diseases. Moreover, the immunomodulatory properties of probiotics have created interest among researchers to explore the therapeutic strategy by activating the immune system against cancerous cells. The present review discusses in detail different strategies and mechanisms of probiotics towards the prevention and treatment of CRC.

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High-frequency homologous recombination between duplicate chromosomal immunoglobulin mu heavy-chain constant regions

Molecular and Cellular Biology ◽

10.1128/mcb.9.12.5500-5507.1989 ◽

1989 ◽

Vol 9 (12) ◽

pp. 5500-5507

Author(s):

M D Baker

Keyword(s):

Homologous Recombination ◽

Heavy Chain ◽

High Frequency ◽

Gene Replacement ◽

Immunoglobulin M ◽

Hybridoma Cells ◽

Immunoglobulin Gene ◽

Reciprocal Recombination ◽

Base Pair Deletion ◽

Frequent Event

Homologous recombination was used in a previous study to correct a 2-base-pair deletion in the third constant domain (Cmu3) of the haploid chromosomal mu gene in a mutant hybridoma cell line by transfer of a pSV2neo vector bearing a subfragment of the normal Cmu region (M.D. Baker, N. Pennell, L. Bosnoyan, and M.J. Shulman, Proc. Natl. Acad. Sci. USA 85:6432-6436, 1988). In these experiments, both gene replacement and single reciprocal crossover events were found to restore normal, cytolytic 2,4,6-trinitrophenyl-specific immunoglobulin M production to the mutant cells. In the cases of single reciprocal recombination, the structure of the recombinant mu gene is such that the normal Cmu region, in its correct position 3' of the expressed 2,4,6-trinitrophenyl-specific heavy-chain variable region, is separated from the mutant Cmu region by the integrated vector sequences. I report here that homologous recombination occurs with high frequency between the duplicate Cmu regions in mitotically growing hybridoma cells. The homologous recombination events were easily detected since they generated hybridomas that were phenotypically different from the parental cells. Analysis of the recombinant cells suggests that gene conversion is the most frequent event, occurring between 60 and 73% of the time. The remaining events consisted of single reciprocal crossovers. Intrachromatid double reciprocal recombination was not detected. The high frequency of recombination, the ability to isolate and analyze the participants in the recombination reactions, and the capacity to generate specific modifications in the immunoglobulin Cmu regions by gene targeting suggest that this system will be useful for studying mammalian chromosomal homologous recombination. Moreover, the ability to specifically modify the chromosomal immunoglobulin genes by homologous recombination should facilitate studies of immunoglobulin gene regulation and expression and provide a more convenient of engineering specifically modified antibody.

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Saccharomyces cerevisiae Rrm3p DNA Helicase Promotes Genome Integrity by Preventing Replication Fork Stalling: Viability of rrm3 Cells Requires the Intra-S-Phase Checkpoint and Fork Restart Activities

Molecular and Cellular Biology ◽

10.1128/mcb.24.8.3198-3212.2004 ◽

2004 ◽

Vol 24 (8) ◽

pp. 3198-3212 ◽

Cited By ~ 97

Author(s):

Jorge Z. Torres ◽

Sandra L. Schnakenberg ◽

Virginia A. Zakian

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Damage ◽

Replication Fork ◽

Opportunity To Learn ◽

Normal Growth ◽

Dna Helicase ◽

S Phase ◽

Exogenous Dna ◽

Fork Stalling ◽

S Phase Checkpoint

ABSTRACT Rrm3p is a 5′-to-3′ DNA helicase that helps replication forks traverse protein-DNA complexes. Its absence leads to increased fork stalling and breakage at over 1,000 specific sites located throughout the Saccharomyces cerevisiae genome. To understand the mechanisms that respond to and repair rrm3-dependent lesions, we carried out a candidate gene deletion analysis to identify genes whose mutation conferred slow growth or lethality on rrm3 cells. Based on synthetic phenotypes, the intra-S-phase checkpoint, the SRS2 inhibitor of recombination, the SGS1/TOP3 replication fork restart pathway, and the MRE11/RAD50/XRS2 (MRX) complex were critical for viability of rrm3 cells. DNA damage checkpoint and homologous recombination genes were important for normal growth of rrm3 cells. However, the MUS81/MMS4 replication fork restart pathway did not affect growth of rrm3 cells. These data suggest a model in which the stalled and broken forks generated in rrm3 cells activate a checkpoint response that provides time for fork repair and restart. Stalled forks are converted by a Rad51p-mediated process to intermediates that are resolved by Sgs1p/Top3p. The rrm3 system provides a unique opportunity to learn the fate of forks whose progress is impaired by natural impediments rather than by exogenous DNA damage.

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Clinic Case of Rare Type VI Osteogenesis Imperfecta

Педиатрическая фармакология ◽

10.15690/pf.v16i1.2001 ◽

2019 ◽

Vol 16 (1) ◽

pp. 30-35

Author(s):

Olga N. Ignatovich ◽

Leyla S. Namazova-Baranova ◽

Tea V. Margieva ◽

Natalia V. Zhurkova ◽

Kirill V. Savostyanov ◽

...

Keyword(s):

Osteogenesis Imperfecta ◽

High Frequency ◽

Heterogeneous Group ◽

Osteogenesis Imperfecta Type ◽

Post Translational Modification ◽

Rare Type ◽

Genes Encoding ◽

Long Time ◽

Collagen Genes

Osteogenesis imperfect is genetically heterogeneous group of diseases which are characterized by bone brittleness and fractures. It was thought for a long time that this is happening due to mutations in collagen genes. However, within past decade the understanding of osteogenesis imperfecta etiology has changed as a result of genetics development. The majority of all cases is related to mutations in collagen genes whereas rare mostly recessive forms are related to mutations in genes encoding collagen post-translational modification. Mutations in SERPINF1 gene were chosen as molecular cause of osteogenesis imperfecta type VI in 2011. Thus the new pathophysiology of this disease was revealed. Children with osteogenesis imperfecta type VI have high-frequency of fractures despite the management with bisphosphonates because mineralized bone osteoid is considerably reduced.

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Mechanism for inverted-repeat recombination induced by a replication fork barrier

Nature Communications ◽

10.1038/s41467-021-27443-w ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Léa Marie ◽

Lorraine S. Symington

Keyword(s):

Replication Fork ◽

Repetitive Sequences ◽

Replication Stress ◽

Yeast Genome ◽

Physical Analysis ◽

Srs2 Helicase ◽

Fork Stalling ◽

Strand Annealing ◽

Recombination Pathway ◽

Stalled Replication Forks

AbstractReplication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. To gain insight into the mechanism of recombination between repeated sequences in the context of replication stress, we used a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome. Our study reveals that the replication fork block stimulates a unique recombination pathway dependent on Rad51 strand invasion and Rad52-Rad59 strand annealing activities, Mph1/Rad5 fork remodelers, Mre11/Exo1/Dna2 resection machineries, Rad1-Rad10 nuclease and DNA polymerase δ. Furthermore, we show recombination at stalled replication forks is limited by the Srs2 helicase and Mus81-Mms4/Yen1 nucleases. Physical analysis of the replication-associated recombinants revealed that half are associated with an inversion of sequence between the repeats. Based on our extensive genetic characterization, we propose a model for recombination of closely linked repeats that can robustly generate chromosome rearrangements.

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