scholarly journals DDRE-14. DE-NOVO PURINE BIOSYNTHESIS IS A MAJOR DRIVER OF CHEMORESISTANCE IN GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i9-i9
Author(s):  
Atique Ahmed
Keyword(s):  
Recurrence Rate ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Negative Regulator ◽  
High Recurrence Rate ◽  
Glioblastoma Cells ◽  
Binding Partner ◽  
De Novo Purine Biosynthesis ◽  
Ciliary Protein ◽  
Adp Ribosylation Factor

Abstract Glioblastoma is a primary brain cancer with a near 100% recurrence rate. Upon recurrence, the tumor is resistant to all conventional therapies, and because of this, 5-year survival is dismal. One of the major drivers of this high recurrence rate is glioblastoma cells’ ability to adapt to complex changes within the tumor microenvironment. To elucidate this adaptation’s molecular mechanisms, specifically during chemotherapy temozolomide, we employed chromatin immunoprecipitation followed by sequencing and gene expression analysis. We identified a molecular circuit in which the expression of ciliary protein ADP-ribosylation factor-like protein 13B (ALR13B) is epigenetically regulated to promote adaptation to chemotherapy. Immuno-precipitation combined with Liquid Chromatography-Mass Spectrometry binding partner analysis revealed that that ARL13B interacts with the purine biosynthetic enzyme inosine-5’-monophosphate dehydrogenase 2 (IMPDH2). Further, radioisotope tracing revealed that this interaction function as a negative regulator for purine salvaging. Inhibition of ARL13B-IMPDH2 interaction enhances temozolomide-induced DNA damage by forcing glioblastoma cells to rely on the purine salvage pathway. Targeting the ARLI3B-IMPDH2 circuit can be achieved using a Food and Drug Administration-approved drug, Mycophenolate Mofetil, that can block the IMPDH2 activity and enhance the therapeutic efficacy of TMZ. Our results suggest and support clinical evaluation of MMF in combination with TMZ treatment in glioma patients.

Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma

2020 ◽  
Vol 12 (547) ◽  
pp. eaay2163
Author(s):  
Madi Y. Cissé ◽  
Samuel Pyrdziak ◽  
Nelly Firmin ◽  
Laurie Gayte ◽  
Maud Heuillet ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Negative Regulator ◽  
Nucleotide Synthesis ◽  
Metabolic Functions ◽  
Xenograft Models ◽  
Well Differentiated ◽  
Serine Metabolism

Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.

Abstract 1473: Identification Of A New NRSF-binding Partner, Zfp90, Which Negatively Regulates The Repression Activity Of NRSF, A Critical Transcriptional Regulator Of Cardiac Fetal Gene Program

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masao Murakami ◽  
Koichiro Kuwahara ◽  
Masaki Harada ◽  
Yasuaki Nakagawa ◽  
Satoru Usami ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dominant Negative ◽  
Assay System ◽  
Negative Regulator ◽  
Binding Partner ◽  
Arrhythmic Death ◽  
Dominant Negative Form ◽  
Cardiac Gene ◽  
Hybrid Screening ◽  
Negative Form

Neuron-restrictive silencer factor, NRSF is a Zn-finger transcription factor that specifically binds to DNA sequence called NRSE to repress the transcription. NRSF is involved in various biological processes, such as neuronal differentiation, carcinogenesis, and cardiac homeostasis. We previously reported that NRSF regulates the transcription of multiple fetal cardiac genes. Cardiac-specific overexpression of a dominant-negative form of NRSF in mice induced reactivation of fetal cardiac gene program, cardiac dysfunction, and sudden arrhythmic death, suggesting NRSF plays important roles in normal cardiac homeostasis. However, the molecular mechanisms or signaling pathways that regulate the activity of NRSF have not been well understood. In an attempt to clarify the regulators of NRSF, we performed yeast two-hybrid screening using NRSF as bait and identified Zfp90 as NRSF-binding protein. NRSF and Zfp90 co-localize in the nuclear, and Zn-finger domain of NRSF specifically interacted with KRAB domain of Zfp90. To monitor the activity of NRSF sensitively, we made NRSF-responsive reporters using NRSE sequence of BNP promoter and established assay system for estimating the NRSF activity. In this assay system, expression of NRSF repressed the reporter activity and co-expression of Zfp90 restored it. Furthermore the expression levels of Zfp90 were elevated in the hearts with cardiomyopathy. These results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to the genetic remodeling during the development of cardiomyopathy..

De-novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

2020 ◽  
Author(s):  
Jack M Shireman ◽  
Fatemeh Atashi ◽  
Gina Lee ◽  
Eunus S. Ali ◽  
Miranda R. Saathoff ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brain Cancer ◽  
De Novo ◽  
Purine Biosynthesis ◽  
Biosynthetic Enzyme ◽  
Salvage Pathway ◽  
Treatment Resistant ◽  
Purine Salvage ◽  
De Novo Purine Biosynthesis ◽  
Ciliary Protein

AbstractThis year nearly 20,000 lives will be lost to Glioblastoma (GBM), a treatment-resistant primary brain cancer. In this study, we identified a molecular circuit driven by epigenetic regulation that regulates the expression of ciliary protein ALR13B. We also demonstrated that ARL13B subsequently interacts with purine biosynthetic enzyme IMPDH2. Removal of ARL13B enhanced TMZ-induced DNA damage by reducing de-novo purine biosynthesis and forcing GBM cells to rely on the purine salvage pathway. Furthermore, targeting can be achieved by using an FDA-approved drug, Mycophenolate Moefitil. Our results suggest a clinical evaluation of MMF in combination with TMZ treatment in glioma patients.

Modern molecular and biological aspects of endometriosis-associated infertility

GYNECOLOGY ◽  
2019 ◽  
Vol 21 (5) ◽  
pp. 12-15
Author(s):  
Anastasiia S Safronova ◽  
Mikhail Yu Vysokikh ◽  
Vladimir D Chuprynin ◽  
Natalia A Buralkina
Keyword(s):  
Signaling Pathways ◽  
Recurrence Rate ◽  
High Recurrence Rate ◽  
Modern Drug ◽  
Surgical Methods ◽  
Prevention And Treatment ◽  
Biological Aspects ◽  
Methods Of Treatment ◽  
New Strategies

There is currently no consensus on the etiopathogenetic nature of endometriosis. The causes of aggressive, progressive, infiltrative growth of endometrioid tissue also remain unclear. An important problem remains the high recurrence rate of endometriosis, despite the availability of modern drug and surgical methods of treatment. The study of the central signaling pathways and the search for new key molecules is of paramount importance for a better understanding of the pathogenesis of the disease, and is also an important step in the development of new strategies for the diagnosis, prevention and treatment of endometriosis.

scholarly journals HP1 drives de novo 3D genome reorganization in early Drosophila embryos

Nature ◽  
2021 ◽  
Author(s):  
Fides Zenk ◽  
Yinxiu Zhan ◽  
Pavel Kos ◽  
Eva Löser ◽  
Nazerke Atinbayeva ◽  
...  
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Early Embryo ◽  
Heterochromatin Protein ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Genome Reorganization

AbstractFundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments. However, the molecular mechanisms that drive de novo organization remain unknown1,2. Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo.

scholarly journals Copy number-dependent DNA methylation of the Pyricularia oryzae MAGGY retrotransposon is triggered by DNA damage

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ba Van Vu ◽  
Quyet Nguyen ◽  
Yuki Kondo-Takeoka ◽  
Toshiki Murata ◽  
Naoki Kadotani ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Rna Silencing ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Pyricularia Oryzae ◽  
Transcriptional Gene Silencing ◽  
Physical Interaction ◽  
Uncharacterized Protein ◽  
Form Complex

AbstractTransposable elements are common targets for transcriptional and post-transcriptional gene silencing in eukaryotic genomes. However, the molecular mechanisms responsible for sensing such repeated sequences in the genome remain largely unknown. Here, we show that machinery of homologous recombination (HR) and RNA silencing play cooperative roles in copy number-dependent de novo DNA methylation of the retrotransposon MAGGY in the fungusPyricularia oryzae. Genetic and physical interaction studies revealed thatRecAdomain-containing proteins, includingP. oryzaehomologs ofRad51, Rad55, andRad57, together with an uncharacterized protein, Ddnm1, form complex(es) and mediate either the overall level or the copy number-dependence of de novo MAGGY DNA methylation, likely in conjunction with DNA repair. Interestingly,P. oryzaemutants of specific RNA silencing components (MoDCL1andMoAGO2)were impaired in copy number-dependence of MAGGY methylation. Co-immunoprecipitation of MoAGO2 and HR components suggested a physical interaction between the HR and RNA silencing machinery in the process.

scholarly journals The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

2021 ◽  
Vol 22 (15) ◽  
pp. 8338
Author(s):  
Asad Jan ◽  
Nádia Pereira Gonçalves ◽  
Christian Bjerggaard Vaegter ◽  
Poul Henning Jensen ◽  
Nelson Ferreira
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Cellular Factors ◽  
Recent Developments ◽  
Novel Targets ◽  
Presynaptic Protein

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

scholarly journals RNA decay in processing bodies is indispensable for adipogenesis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Ryotaro Maeda ◽  
Daisuke Kami ◽  
Akira Shikuma ◽  
Yosuke Suzuki ◽  
Toshihiko Taya ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Adipogenic Differentiation ◽  
Negative Regulator ◽  
Translational Repression ◽  
Rna Decay ◽  
Significant Suppression ◽  
Intracellular Lipid ◽  
Processing Bodies ◽  
Binding Partner ◽  
The Stability

AbstractThe RNA decay pathway plays key regulatory roles in cell identities and differentiation processes. Although adipogenesis is transcriptionally and epigenetically regulated and has been thoroughly investigated, how RNA metabolism that contributes to the stability of phenotype-shaping transcriptomes participates in differentiation remains elusive. In this study, we investigated Ddx6, an essential component of processing bodies (PBs) that executes RNA decay and translational repression in the cytoplasm and participates in the cellular transition of reprogramming. Upon adipogenic induction, Ddx6 dynamically accumulated to form PBs with a binding partner, 4E-T, at the early phase prior to emergence of intracellular lipid droplets. In contrast, preadipocytes with Ddx6 knockout (KO) or 4E-T knockdown (KD) failed to generate PBs, resulting in significant suppression of adipogenesis. Transcription factors related to preadipocytes and negative regulators of adipogenesis that were not expressed under adipogenic stimulation were maintained in Ddx6-KO and 4E-T-KD preadipocytes under adipogenic induction. Elimination of Dlk1, a major negative regulator of adipogenesis, in 3T3L1 Ddx6-KO cells did not restore adipogenic differentiation capacity to any extent. Similar to murine cells, human primary mesenchymal stem cells, which can differentiate into adipocytes upon stimulation with adipogenic cocktails, required DDX6 to maturate into adipocytes. Therefore, RNA decay of the entire parental transcriptome, rather than removal of a strong negative regulator, could be indispensable for adipogenesis.

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