scholarly journals Mechanistic insights into KDM4A driven genomic instability

2021 ◽  
Author(s):  
Nicolas L. Young ◽  
Ruhee Dere
Keyword(s):  
Genomic Instability ◽  
Methylation Status ◽  
Histone H3 ◽  
Checkpoint Control ◽  
Cellular Processes ◽  
Chromosomal Breaks ◽  
Transcriptional Modulation ◽  
Epigenetic Signatures ◽  
Mitotic Disturbances

Alterations in global epigenetic signatures on chromatin are well established to contribute to tumor initiation and progression. Chromatin methylation status modulates several key cellular processes that maintain the integrity of the genome. KDM4A, a demethylase that belongs to the Fe-II dependent dioxygenase family that uses α-ketoglutarate and molecular oxygen as cofactors, is overexpressed in several cancers and is associated with an overall poor prognosis. KDM4A demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. Given the complexity that exists with these marks on chromatin and their effects on transcription and proliferation, it naturally follows that demethylation serves an equally important role in these cellular processes. In this review, we highlight the role of KDM4A in transcriptional modulation, either dependent or independent of its enzymatic activity, arising from the amplification of this demethylase in cancer. KDM4A modulates re-replication of distinct genomic loci, activates cell cycle inducers, and represses proteins involved in checkpoint control giving rise to proliferative damage, mitotic disturbances and chromosomal breaks, ultimately resulting in genomic instability. In parallel, emerging evidence of non-nuclear substrates of epigenetic modulators emphasize the need to investigate the role of KDM4A in regulating non-nuclear substrates and evaluate their contribution to genomic instability in this context. The existence of promising KDM-specific inhibitors makes these demethylases an attractive target for therapeutic intervention in cancers.

scholarly journals Inactivation of 14-3-3ς Influences Telomere Behavior and Ionizing Radiation-Induced Chromosomal Instability

2000 ◽  
Vol 20 (20) ◽  
pp. 7764-7772 ◽  
Author(s):  
Sonu Dhar ◽  
Jeremy A. Squire ◽  
M. Prakash Hande ◽  
Raymund J. Wellinger ◽  
Tej K. Pandita
Keyword(s):  
Dna Sequences ◽  
Nuclear Matrix ◽  
Mammalian Cells ◽  
Eukaryotic Cell ◽  
Checkpoint Control ◽  
Aberrant Chromosome ◽  
M Phase ◽  
Chromosomal Breaks ◽  
Radiation Induced

ABSTRACT Telomeres are complexes of repetitive DNA sequences and proteins constituting the ends of linear eukaryotic chromosomes. While these structures are thought to be associated with the nuclear matrix, they appear to be released from this matrix at the time when the cells exit from G2 and enter M phase. Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. The 14-3-3ς gene has been reported to be a checkpoint control gene, since it promotes G2 arrest following DNA damage. Here we demonstrate that inactivation of this gene influences genome integrity and cell survival. Analyses of chromosomes at metaphase showed frequent losses of telomeric repeat sequences, enhanced frequencies of chromosome end-to-end associations, and terminal nonreciprocal translocations in 14-3-3ς−/− cells. These phenotypes correlated with a reduction in the amount of G-strand overhangs at the telomeres and an altered nuclear matrix association of telomeres in these cells. Since the p53-mediated G1 checkpoint is operative in these cells, the chromosomal aberrations observed occurred preferentially in G2 after irradiation with gamma rays, corroborating the role of the 14-3-3ς protein in G2/M progression. The results also indicate that even in untreated cycling cells, occasional chromosomal breaks or telomere-telomere fusions trigger a G2 checkpoint arrest followed by repair of these aberrant chromosome structures before entering M phase. Since 14-3-3ς−/− cells are defective in maintaining G2 arrest, they enter M phase without repair of the aberrant chromosome structures and undergo cell death during mitosis. Thus, our studies provide evidence for the correlation among a dysfunctional G2/M checkpoint control, genomic instability, and loss of telomeres in mammalian cells.

scholarly journals The N-Terminal Tail of Histone H3 Regulates Copper Homeostasis in Saccharomyces cerevisiae

2020 ◽  
Author(s):  
Sakshi Singh ◽  
Rakesh Kumar Sahu ◽  
Raghuvir Singh Tomar
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Gene Regulation ◽  
Transcriptional Regulation ◽  
Histone H3 ◽  
Copper Homeostasis ◽  
Tata Binding Protein ◽  
Copper Stress ◽  
Toxic Level ◽  
Cellular Processes

Copper homeostasis is crucial for cellular processes. The balance between nutritional and toxic level is maintained through the regulation of uptake, distribution and detoxification via antagonistic actions of two transcription factors AceI and Mac1. AceI responds to toxic copper levels by transcriptional regulation of detoxification genes CUP1 and CRS5. Cup1 metallothionein (MT) confers protection against toxic copper levels. CUP1 gene regulation is a multifactorial event requiring AceI, TBP (TATA-binding protein), chromatin remodeler, acetyltransferase (Spt10) and histones. However, the role of histone H3 residues has not been fully elucidated. To investigate the role of H3 tail in CUP1 transcriptional regulation, we screened the library of histone mutants in copper stress. We identified mutations in H3 (K23Q, K27R, K36Q, Δ5-16, Δ13-16, Δ13-28, Δ25-28, Δ28-31, Δ29-32) that reduce CUP1 expression. We detected reduced AceI occupancy across CUP1 promoter in K23Q, K36Q, Δ5-16, Δ13-28, Δ25-28 and Δ28-31 correlating with the reduced CUP1 transcription. Majority of these mutations affect TBP occupancy at CUP1 promoter augmenting the CUP1 transcription defect. Additionally, some mutants display cytosolic protein aggregation upon copper stress. Altogether, our data establish previously unidentified residues of H3 N-terminal tail and their modifications in CUP1 regulation.

2 Role of histone H3 lysine 9 trimethylation during bovine pre-implantation embryonic development

2019 ◽  
Vol 31 (1) ◽  
pp. 126
Author(s):  
M. Navarro ◽  
C. Bluguermann ◽  
M. Von Meyeren ◽  
V. Bariani ◽  
C. Osycka ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Mammalian Species ◽  
Methylation Status ◽  
Histone H3 ◽  
Germinal Vesicle ◽  
Data Set ◽  
Guide Rna ◽  
Rna Targeting ◽  
Student’S T

Histones play an important role in DNA’s compaction and organisation into the cellular nucleus. Depending on which histone modification occurs, chromatin can take a conformation of heterochromatin or euchromatin, which are associated with gene repression or expression, respectively. Histone H3 lysine 9 (H3K9) trimethylation (H3K9me3) is associated with gene silencing. At least 3 methyltransferases are able to change the methylation status of H3K9: SUV39H1, SUV39H2, and SETDB1. In several mammalian species, modulation of H3K9 methylation status has been demonstrated to be necessary to achieve a successful pre-implantation embryonic development after IVF or somatic cell NT. The aim of this work was to study the role of H3K9me3 in IVF pre-implantation bovine embryos. For this purpose, immunostaining of H3K9me3 at different pre-implantation stages of development was performed. Further, the relative abundances of the methyltransferases SUV39H1 and SUV39H2 were measured by real-time PCR using luciferase transcript as an exogenous gene for normalization. Finally, to evaluate H3K9me3 involvement during pre-implantation embryonic development, we generated SUV39H1 or SUV39H2 knockout embryos by the CRISPR/Cas9 system. We designed guide RNA targeting SUV39H1 or SUV39H2 and co-injected the presumptive zygote’s cytoplasm 18h post-fertilization with Cas9 protein. At Day 8 post-fertilization, the number of blastocysts was assessed and embryos were immunostained to evaluate H3K9me3. Results were analysed using Student’s t-test or ANOVA with the post-hoc Tukey test depending on data set (P ≤ 0.05) and reported as means±standard errors of the mean. Oocytes at germinal vesicle stage and metaphase II as well as embryos at different stages of pre-implantation development (2, 4, and 8 cells, morula, and blastocyst; n=6) were immunoreactive for H3K9me3. Expression of SUV39H1 and SUV39H2 mRNA decreased significantly as embryonic development progressed, reaching undetectable levels at stages where genome activation had already occurred (morula and blastocyst; P<0.0001, n=3). When zygotes were co-injected with the guide RNA targeting SUV39H1/Cas9, embryonic production showed a significant increase compared with the control [42.26%±5.03 (28/65) v. 23.86%±3.99 (21/88), respectively; P=0.034, n=4], and H3K9me3 immunostaining was reduced in treated embryos. Editing efficiency was estimated at 66%. In contrast, no statistical differences were found in embryonic production or H3K9me3 immunostaining in embryos co-injected with the guide RNA targeting SUV39H2/Cas9 (P=0.57, n=3). In conclusion, we were able to characterise H3K9me3 and determine transcript levels of methyltransferases SUV39H1 and SUV39H2 in oocytes and different stages of pre-implantation embryonic development. We also demonstrated that SUV39H1 deletion led to an increased embryonic production, suggesting that H3K9me3 removal would allow a greater relaxation of the heterochromatin and consequently a successful activation of embryonic genes. This highlights the essential role of H3K9me3 during bovine pre-implantation embryonic development.

Dysregulation of HOX as a Potential Therapeutic Target in Breast Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ji-Yeon Lee ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Hox Genes ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Genome Structure ◽  
Control Cell ◽  
Three Dimensional ◽  
Cellular Processes ◽  
Hox Protein

: HOX genes belong to the highly conserved homeobox superfamily, responsible for the regulation of various cellular processes that control cell homeostasis, from embryogenesis to carcinogenesis. The abnormal expression of HOX genes is observed in various cancers, including breast cancer; they act as oncogenes or as suppressors of cancer, according to context. In this review, we analyze HOX gene expression patterns in breast cancer and examine their relationship, based on the three-dimensional genome structure of the HOX locus. The presence of non-coding RNAs, embedded within the HOX cluster, and the role of these molecules in breast cancer have been reviewed. We further evaluate the characteristic activity of HOX protein in breast cancer and its therapeutic potential.

MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

2020 ◽  
Vol 26 ◽  
Author(s):  
Yini Ma ◽  
Xiu Cao ◽  
Guojuan Shi ◽  
Tianlu Shi
Keyword(s):  
Digestive System ◽  
Target Genes ◽  
Malignant Neoplasm ◽  
Vital Role ◽  
Diagnostic Biomarkers ◽  
Cellular Processes ◽  
Promising Therapeutic Target ◽  
Direct Target ◽  
Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

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