Risks of recombinant DNA regulations.
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DNA, Recombinant↗
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Results for “DNA regulator”
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DNA synthesis control in yeast: an evolutionarily conserved mechanism for regulating DNA synthesis genes?
After yeast cells commit to the cell cycle in a process called START, genes required for DNA synthesis are expressed in late G1. Periodicity is mediated by a hexameric sequence, known as a MCB element, present in all DNA synthesis gene promoters. A complex that specifically binds MCBs has been identified. One polypeptide in the MCB complex is Swi6, a transcription factor that together with Swi4 also binds G1 cyclin promoters and participates in a positive feedback loop at START. The finding that Swi6 is directly involved in both START and DNA synthesis gene control suggest a model in which Swi6, activated through its participation in START, serves as the central transcription factor in coordinating late G1 gene expression. The mechanism may be conserved in all eukaryotic cells.
Animals↗
Transposition element MERVL regulates DNA demethylation through TET3 in oxidative-damaged mouse preimplantation embryos.
Transposable elements (TEs) comprise approximately half of eukaryotic genomes and significantly contribute to genome plasticity. In this study, we focused on a specific TE, MERVL, which exhibits particular expression during the 2-cell stage and commonly serves as an indicator of embryonic totipotency. However, its precise role in embryo development remains mysterious. We utilized DRUG-seq to investigate the effects of oxidative damage on genes and TEs expression. Our findings revealed that exposure to hydrogen peroxide (H2O2) could induce DNA damage, apoptosis, and incomplete DNA demethylation in embryos, which were potentially associated with MERVL expression. To further explore its function, antisense nucleotides (ASO) targeting MERVL were constructed to knockdown the expression in early embryos. Notably, this knockdown led to the occurrence of DNA damage and apoptosis as early as the 2-cell stage, consequently reducing the number of embryos that could progress to the blastocyst stage. Moreover, we discovered that MERVL exerted an influence on the reprogramming of embryonic DNA methylation. In MERVL-deficient embryos, the activity of the DNA demethylase ten-eleven translocation 3 (TET3) was suppressed, resulting in impaired demethylation when compared to normal development. This impairment might underpin the mechanism that impacts embryonic development. Collectively, our study not only verified the crucial role of MERVL in embryonic development but also probed its regulatory function in DNA methylation reprogramming, thereby laying a solid foundation for further investigations into MERVL's role.
Animals↗
Let us stop regulating DNA research.
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DNA, Bacterial↗
RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.
TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.
Amyotrophic lateral sclerosis↗
Morphine regulates DNA synthesis in rat cerebellar neuroblasts in vitro.
The effects of morphine on DNA synthesis by external granular layer (EGL) neuroblasts was examined in whole-mount organotypic cultures isolated from 10-day-old rat cerebella using bromodeoxyuridine (BrdU). After 24 h in vitro, explants were treated for 24 h with 10 nM, 1 or 100 microM morphine, morphine plus 30 nM, 3 or 300 microM of the opiate antagonist naloxone, respectively, or those concentrations of naloxone alone. BrdU was added during the last 4 h of drug treatment. EGL neuroblasts were unambiguously identified by size and morphology, location and by protein kinase C II immunocytochemistry. The proportion of EGL neuroblasts incorporating BrdU was significantly reduced in the presence of 1 microM morphine, while 100 microM morphine had little additional effect. The concentration of morphine predicted to cause a half-maximal reduction in BrdU labeling index was 22.5 nM. Morphine's ability to reduce BrdU incorporation by EGL neuroblasts was concentration dependent and was prevented by concomitant treatment with naloxone, implicating the involvement of opioid receptors. The results suggest that morphine can directly regulate the growth of the developing cerebellum by inhibiting neuroblast proliferation within the EGL.
Animals↗
Thymic factors regulating DNA synthesis in lymphocytes cultured in vitro.
An extract was prepared from the calf thymus. Thymic factors with stimulating or inhibiting effect on the incorporation of 3H-thymidine into DNA of cultured lymphocytes from guinea pigs and rats were identified and separated from each other by ultrafiltration, gel filtration, ion-exchange chromatography and electrofocusing. Two different stimulating substances were found both with molecular weight below 10,000 daltons. The result of ion-exchange chromatography and preparative electrofocusing indicated the existence of one (or two) acidic and one slightly alkaline stimulating thymic factor. The stimulating substances were found in greater amount in a young thymus than in a an old one. the thymic factors increasing the uptake of 3H-thymidine are probably polypeptides.
Cell Survival↗
Selective control of DNA helix openings during gene regulation.
DNA helices must undergo openings in the form of localized strand separations in order to permit the onset of RNA synthesis or DNA synthesis. The selective control of such DNA helix openings at particular gene loci is the critical feature of gene regulation in prokaryotes and eukaryotes.
Animals↗
Regulation of DNA replication by the nuclear envelope.
Recent evidence suggests that the nuclear envelope is directly involved in regulating DNA replication. It does this in at least three ways. First, replication is dependent on assembly of an intact nuclear envelope capable of nuclear transport. Second, the nuclear membrane defines the nucleus as the fundamental unit of replication and determines the timing of initiation. Third, the nuclear membrane is essential for coupling DNA replication to the cell cycle. Thus, regulated DNA replication in eukaryotic cells depends on a structurally intact and functional nuclear envelope.
Animals↗
Regulation of DNA Topology in Archaea: State of the Art and Perspectives.
DNA topology is a direct consequence of the double helical nature of DNA and is defined by how the two complementary DNA strands are intertwined. Virtually every reaction involving DNA is influenced by DNA topology or has topological effects. It is therefore of fundamental importance to understand how this phenomenon is controlled in living cells. DNA topoisomerases are the key actors dedicated to the regulation of DNA topology in cells from all domains of life. While significant progress has been made in the last two decades in understanding how these enzymes operate in vivo in Bacteria and Eukaryotes, studies in Archaea have been lagging behind. This review article aims to summarize what is currently known about DNA topology regulation by DNA topoisomerases in main archaeal model organisms. These model archaea exhibit markedly different lifestyles, genome organization and topoisomerase content, thus highlighting the diversity and the complexity of DNA topology regulation mechanisms and their evolution in this domain of life. The recent development of functional genomic assays supported by next-generation sequencing now allows to delve deeper into this timely and exciting, yet still understudied topic.
Archaea↗
elk-1 domains responsible for autonomous DNA binding, SRE:SRF interaction and negative regulation of DNA binding.
The ets oncogene superfamily consists of a family of sequence-specific DNA-binding transcriptional activator proteins. We have previously identified, cloned and characterized one of the divergent ets-related members elk-1 and shown that it codes for a sequence-specific DNA-binding transcriptional activator. We have also shown that elk-1 forms SRF (Serum Response Factor) dependent ternary complex with SRE (Serum Response Element), similar to p62TCF. In this report, we have mapped the DNA-binding domain of the elk-1 protein (EDB, elk-1 DNA Binding domain) to the 76 amino acid ets homology region. We have also mapped the SRF interaction domain of the elk-1 protein (ESI, elk-1 SRF Interaction domain) to the carboxy-terminal region of the EDB domain. Ternary complex formation by elk-1 requires both EDB and ESI domains of the elk-1 protein. Our results also show that the EDB domain of the elk-1 protein (residues 1-89) binds SRE autonomously, unlike full-length elk-1 protein, suggesting the presence of a potential Negative Regulatory DNA binding domain (NRD) which prevents the binding of elk-1 protein to SRE. Interaction of SRF with the ESI domain allows the elk-1 protein to bind to SRE. Thus elk-1 belongs to a class of transcriptional factors that are involved in gene regulation not only by autonomous DNA binding but also by indirect DNA binding through recruitment by cellular factors.
DNA↗
Regulation of DNA replication on subchromosomal units of mammalian cells.
The regulation of DNA replication at a subchromosomal level in mammalian cells has been investigated. DNA fiber autoradiographs were prepared from mouse L-929 cells pulse labeled with (3H)thymidine. Initiation events and subsequent chain growth occurring over short stretches (up to three replication units in length) of chromosomal DNA were analyzed. The results show that adjacent units usually initiate replication synchronously and that this synchrony is related to the proximity of initiation sites. In addition, adjacent units are of similar size and the rates of replication fork progression within units and on adjacent units are similar. The rate of fork progression increases with increasing replication unit size. Finally, no evidence for fixed termination sites for the units has been found. These observations suggest that despite large variations in size of replication units, timing of initiation events, and rates of fork progression found in chromosomal DNA as a whole, these processes are closely regulated within subchromosomal clusters of active replication units.
Animals↗
Regulation of DNA replication in S phase nuclei by ATP and ADP pools.
Synchronized 3T6 (mouse fibroblast) ghost monolayers (isolated nuclei) were utilized to study the effects of ATP and ADP levels on DNA replication in vitro. A system yielding discontinuous semiconservative DNA replication (without any detectable repair) in synchronized S phase nuclei has been developed. Lack of initiation of new sites has been observed in isolated S phase 3T6 nuclei without the presence of cytoplasmic material; DNA synthesis is comprised only of elongation at sites where initiation had previously taken place. DNA synthesis in S phase nuclei proceeded optimally at an ATP concentration of 4-5 mM. High ATP levels as well as high ATP/ADP ratios (produced by an ATP-regenerating system at a variety of ATP concentrations) yielded marked inhibition of [(3)H]dTTP incorporation. The cellular and nuclear pools of ATP and ADP in intact synchronized 3T6 cells were accurately determined by high-pressure liquid chromatography. A good correlation with the studies on isolated nuclei has been observed. Whereas total cellular ATP pools increase during the progression of 3T6 cells from G(1) to S phase of the cell cycle, nuclear ATP pools do not increase, and the nuclear ATP/ADP ratios decrease once the cells enter the S phase of their cycle. These experiments suggest that nuclear ATP pools and ATP/ADP ratios act as S phase controls, regulating DNA elongation at sites where its synthesis has previously been initiated by cytoplasmic factors.
Adenosine Diphosphate↗
Regulation of DNA chain elongation in SV3T3 cells in relation to growth rate.
Regulation of DNA synthesis was investigated in SV40 transformed 3T3 cells exhibiting variable growth rates and residence times in S phase when cultured in the presence of different serum concentrations. Pulse-labeled DNA was chased into large molecular weight material in vivo much more slowly in slowly growing cells than in cells growing at the normal rate. Consistent with this, the joining of short (less than 10 S) chains to form long (greater than 10 S) chains by whole cell lysate system in vitro was greatly impaired in slowly growing cells compared to controls. Thus the lengthening of S phase in SV3T3 cells growing slowly in low serum is reflected in a reduced rate of DNA chain elongation. The presence of cycloheximide during chase in vivo reduced the rate of conversion of pulse-labeled molecules into large molecular weight DNA in both slowly growing and normally growing cells.
Cell Cycle↗
Genome-wide DNA methylation regulation analysis provides novel insights on post-radiation breast cancer.
Breast cancer (BC) is the most common malignancy with a poor prognosis. Radiotherapy is one of the leading traditional treatments for BC. However, radiotherapy-associated secondary diseases are severe issues for the treatment of BC. The present study integrated multi-omics data to investigate the molecular and epigenetic mechanisms involved in post-radiation BC. The differences in the expression of radiation-associated genes between post-radiation and pre-radiation BC samples were determined. Enrichment analysis revealed that these radiation-associated genes involved diverse biological functions and pathways in BC. Combining epigenetic data, we identified radiation-associated genes whose transcriptional changes might be associated with aberrant methylation. Then, we identified potential therapeutic targets and chemical drugs for post-radiation BC patient treatment by constructing a drug-target association network. Specifically, four radiation-associated genes (CD248, CCDC80, GADD45B, and MMP2) whose increased expression might be regulated by hypomethylation of the corresponding enhancer region were found to have excellent diagnostic effects and clinical prognostic value. Finally, we further used independent samples to verify CD248 expression and established a simple epigenetic regulatory model. In summary, this study provides novel insights for understanding the regulation of target genes mediated by DNA methylation and developing potential biomarkers for radiation-associated secondary diseases in BC.
Humans↗
MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.
BACKGROUND/OBJECTIVES: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. METHODS: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. RESULTS: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. CONCLUSIONS: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.
ATR↗
MDR1 DNA glycosylase regulates the expression of genomically imprinted genes and Helitrons.
Targeted demethylation by DNA glycosylases (DNGs) results in differential methylation between parental alleles in the endosperm, which drives imprinted expression. Here, we performed RNA sequencing on endosperm derived from DNG mutant mdr1 and wild-type (WT) endosperm. Consistent with the role of DNA methylation in gene silencing, we find 108 genes and 96 TEs differentially expressed (DE) transcripts that lost expression in the hypermethylated mdr1 mutant. Compared with other endosperm transcripts, the mdr1 targets are enriched for TEs (particularly Helitrons), and DE genes are depleted for both core genes and GO term assignments, suggesting that the majority of DE transcripts are TEs and pseudo-genes. By comparing DE genes to imprinting calls from prior studies, we find that the majority of DE genes have maternally biased expression, and approximately half of all maternally expressed genes (MEGs) are DE in this study. In contrast, no paternally expressed genes (PEGs) are DE. DNG-dependent imprinted genes are distinguished by maternal demethylation and expression primarily in the endosperm, so we also performed Enzymatic Methyl-seq on hybrids to identify maternal demethylation and utilized a W22 gene expression atlas to identify genes expressed primarily in the endosperm. Overall, approximately ⅔ of all MEGs show evidence of regulation by DNGs. Taken together, this study solidifies the role of MDR1 in the regulation of maternally expressed, imprinted genes and TEs and identifies subsets of genes with DNG-independent imprinting regulation.
Genomic Imprinting↗
Role of the simian virus 40 gene A product in regulation of DNA synthesis in transformed cells.
Cells transformed by tsA mutants of simian virus 40 (SV40) are temperature sensitive for the maintenance of the transformed phenotype. The kinetics of induction of DNA synthesis were determined for hamster cell transformants shifted to the permissive temperature after a 48-h serum arrest at the nonpermissive temperature. DNAsynthesis was initiated in the tsA transformants by 8 h after shiftdown was maximal by 12 h. The presence or absence of fetal bovine serum at the time of temperature shift had no effect on the kinetics of initiation of DNA synthesis. Analysis of TTP in tsA transformants revealed similar levels of incorporation of [3H]thymidine into TTP at both permissive and nonpermissive temperatures. Autoradiography revealed that by 12 h after a shift to the permissive temperature, approximately 50% of the cells exhibited labeled nuclei after a 60-min pulse with [3H]thymidine, indicating that a majority of the cells were actively synthesizing DNA. By 8 to 12 h after a shiftup of confluent tsA transformants to the nonpermissive temperature, the number of labeled nuclei was reduced to approximately 16%, regardless of serum concentration. These data indicate that the SV40 gene A product, either directly or indirectly, regulates cellular DNA synthesis in transformed cells.
Cell Line↗