scholarly journals Mutational signature SBS8 predominantly arises due to late replication errors in cancer

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Vinod Kumar Singh ◽  
Arnav Rastogi ◽  
Xiaoju Hu ◽  
Yaqun Wang ◽  
Subhajyoti De
Keyword(s):  
Dna Repair ◽  
Cancer Progression ◽  
Replication Timing ◽  
Cell Types ◽  
Late Replication ◽  
Multiple Cancer ◽  
Mutational Signatures ◽  
Replication Errors ◽  
Mutational Signature ◽  
Multiple Cell

AbstractAlthough a majority of somatic mutations in cancer are passengers, their mutational signatures provide mechanistic insights into mutagenesis and DNA repair processes. Mutational signature SBS8 is common in most cancers, but its etiology is debated. Incorporating genomic, epigenomic, and cellular process features for multiple cell-types we develop genome-wide composite epigenomic context-maps relevant for mutagenesis and DNA repair. Analyzing somatic mutation data from multiple cancer types in their epigenomic contexts, we show that SBS8 preferentially occurs in gene-poor, lamina-proximal, late replicating heterochromatin domains. While SBS8 is uncommon among mutations in non-malignant tissues, in tumor genomes its proportions increase with replication timing and speed, and checkpoint defects further promote this signature - suggesting that SBS8 probably arises due to uncorrected late replication errors during cancer progression. Our observations offer a potential reconciliation among different perspectives in the debate about the etiology of SBS8 and its relationship with other mutational signatures.

scholarly journals Current Understanding of Exosomal MicroRNAs in Glioma Immune Regulation and Therapeutic Responses

2022 ◽  
Vol 12 ◽  
Author(s):  
Jinwu Peng ◽  
Qiuju Liang ◽  
Zhijie Xu ◽  
Yuan Cai ◽  
Bi Peng ◽  
...  
Keyword(s):  
Immune Regulation ◽  
Response Prediction ◽  
Cell Types ◽  
Clinicopathological Characteristics ◽  
The Novel ◽  
Multiple Cancer ◽  
Exosomal Mirnas ◽  
Multiple Cell ◽  
Almost All ◽  
Therapeutic Responses

Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication via transferring diverse biomolecules. Recently, microRNAs (miRNAs) were demonstrated to be enclosed in exosomes and therefore was protected from degradation. Such exosomal miRNAs can be transmitted to recipient cells where they could regulate multiple cancer-associated biological processes. Accumulative evidence suggests that exosomal miRNAs serve essential roles in modifying the glioma immune microenvironment and potentially affecting the malignant behaviors and therapeutic responses. As exosomal miRNAs are detectable in almost all kinds of biofluids and correlated with clinicopathological characteristics of glioma, they might be served as promising biomarkers for gliomas. We reviewed the novel findings regarding the biological functions of exosomal miRNAs during glioma pathogenesis and immune regulation. Furthermore, we elaborated on their potential clinical applications as biomarkers in glioma diagnosis, prognosis and treatment response prediction. Finally, we summarized the accessible databases that can be employed for exosome-associated miRNAs identification and functional exploration of cancers, including glioma.

Genomic instability in cancer: molecular mechanisms and therapeutic potentials

2021 ◽  
Vol 27 ◽  
Author(s):  
Arash Salmaninejad ◽  
Khandan Ilkhani ◽  
Havva Marzan ◽  
Jamshid Gholizadeh Navashenaq ◽  
Samira Rahimirad ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genomic Instability ◽  
Chromosomal Instability ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Dna Damages ◽  
Replication Errors ◽  
Repair Mechanisms ◽  
Dna Replication Errors

: DNA damage usually happens in all cell types, which may originate from endogenous sources, (i.e., DNA replication errors) or be emanated from radiations or chemicals. These damages range from changes in few nucleotides to large structural abnormalities on chromosomes and, if not repaired, could disturb the cellular homeostasis or cause cell death. DNA repair, as the most significant response to DNA damage, provides biological pathways by which DNA damages are corrected and returned into their natural circumstance. However, aberration in the DNA repair mechanisms may result in genomic and chromosomal instability and the accumulation of mutations. The activation of oncogenes and/or inactivation of tumor suppressor genes are serious consequence of genomic and chromosomal instability and may bring the cells into a cancerous phenotype. Therefore, genomic and chromosomal instability is usually considered as a crucial factor in the carcinogenesis and an important hallmark of various human malignancies. In the present study, we review our current understanding of the most updated mechanisms underlying genomic instability in cancer and discuss about the potential promises of these mechanisms in finding new targets for the treatment of cancer.

scholarly journals Evidence of a Prion-Like Transmission of p53 Amyloid in Saccharomyces cerevisiae

2017 ◽  
Vol 37 (18) ◽  
Author(s):  
Shinjinee Sengupta ◽  
Samir K. Maji ◽  
Santanu K. Ghosh
Keyword(s):  
Cancer Progression ◽  
Rational Design ◽  
P53 Protein ◽  
Cell Types ◽  
Mutant P53 ◽  
Loss Of Function ◽  
Multiple Cancer ◽  
Aggregation Inhibitors ◽  
Specific Peptide

ABSTRACT Loss of p53 function is largely responsible for the occurrence of cancer in humans. Aggregation of mutant p53 has been found in multiple cancer cell types, suggesting a role of aggregation in loss of p53 function and cancer development. The p53 protein has recently been hypothesized to possess a prion-like conformation, although experimental evidence is lacking. Here, we report that human p53 can be inactivated upon exposure to preformed fibrils containing an aggregation-prone sequence-specific peptide, PILTIITL, derived from p53, and the inactive state was found to be stable for many generations. Importantly, we provide evidence of a prion-like transmission of these p53 aggregates. This study has significant implications for understanding cancer progression due to p53 malfunctioning without any loss-of-function mutation or occurrence of transcriptional inactivation. Our data might unlock new possibilities for understanding the disease and will lead to rational design of p53 aggregation inhibitors for the development of drugs against cancer.

scholarly journals A p38 MAPK regulated MEF2:β-catenin interaction enhances canonical Wnt signalling

2015 ◽  
pp. MCB.00832-15 ◽  
Author(s):  
Saviz Ehyai ◽  
Mathew G. Dionyssiou ◽  
Joseph W. Gordon ◽  
Declan Williams ◽  
K. W. Michael Siu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
P38 Mapk ◽  
Cancer Progression ◽  
Cross Talk ◽  
Cell Types ◽  
Wnt Signalling ◽  
Nuclear Accumulation ◽  
Mapk Signalling ◽  
Multiple Cell ◽  
Canonical Wnt

Canonical Wnt/β-catenin signalling plays a major role in various biological contexts such as embryonic development, cell proliferation, and cancer progression.. Previously, a connection between p38 MAPK signalling and Wnt-mediated activation of β-catenin has been implied but poorly understood. In this study, we investigate potential cross talk between p38 MAPK and Wnt/β-catenin signalling. Here, we show that loss of p38 MAPK α/β function reduces β-catenin nuclear accumulation in Wnt3a stimulated primary vascular smooth muscle cells (VSMCs). Conversely, active p38 MAPK signalling increases β-catenin nuclear localization and target gene activity in multiple cell types. Furthermore, the effect of p38 MAPK α/β on β-catenin activity is mediated through phosphorylation of a key p38 MAPK target, myocyte enhancer factor 2 (MEF2). Here, we report a p38 MAPK mediated phosphorylation-dependent interaction between MEF2 and β-catenin in multiple cell types and primary VSMCs, resulting in: (a) increased β-catenin nuclear retention, which is reversed by siRNA mediated MEF2 gene silencing; (b) increased activation of MEF2 and Wnt/β-catenin target genes, and; (c) increased Wnt stimulated cell proliferation. These observations provide mechanistic insight into a fundamental level of cross talk between p38 MAPK/MEF2 signalling and canonical Wnt signalling.

scholarly journals A framework for mutational signature analysis based on DNA shape parameters

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262495
Author(s):  
Aleksandra Karolak ◽  
Jurica Levatić ◽  
Fran Supek
Keyword(s):  
Dna Repair ◽  
Base Pair ◽  
Mutation Frequency ◽  
Structural Features ◽  
Sequence Motif ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Radiation Chemical ◽  
Mutational Signature ◽  
Dna Shape

The mutation risk of a DNA locus depends on its oligonucleotide context. In turn, mutability of oligonucleotides varies across individuals, due to exposure to mutagenic agents or due to variable efficiency and/or accuracy of DNA repair. Such variability is captured by mutational signatures, a mathematical construct obtained by a deconvolution of mutation frequency spectra across individuals. There is a need to enhance methods for inferring mutational signatures to make better use of sparse mutation data (e.g., resulting from exome sequencing of cancers), to facilitate insight into underlying biological mechanisms, and to provide more accurate mutation rate baselines for inferring positive and negative selection. We propose a conceptualization of mutational signatures that represents oligonucleotides via descriptors of DNA conformation: base pair, base pair step, and minor groove width parameters. We demonstrate how such DNA structural parameters can accurately predict mutation occurrence due to DNA repair failures or due to exposure to diverse mutagens such as radiation, chemical exposure, and the APOBEC cytosine deaminase enzymes. Furthermore, the mutation frequency of DNA oligomers classed by structural features can accurately capture systematic variability in mutagenesis of >1,000 tumors originating from diverse human tissues. A nonnegative matrix factorization was applied to mutation spectra stratified by DNA structural features, thereby extracting novel mutational signatures. Moreover, many of the known trinucleotide signatures were associated with an additional spectrum in the DNA structural descriptor space, which may aid interpretation and provide mechanistic insight. Overall, we suggest that the power of DNA sequence motif-based mutational signature analysis can be enhanced by drawing on DNA shape features.

scholarly journals The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinyan Wang ◽  
Lijuan Chen ◽  
Ping Qiang
Keyword(s):  
Rna Binding ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Cancer Prognosis ◽  
Messenger Rnas ◽  
Multiple Cancer ◽  
Multiple Cell ◽  
Mrna Binding ◽  
Post Transcriptional Regulation

AbstractThe human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2/IMP2) is an RNA-binding protein that regulates multiple biological processes. Previously, IGF2BP2 was thought to be a type 2 diabetes (T2D)-associated gene. Indeed IGF2BP2 modulates cellular metabolism in human metabolic diseases such as diabetes, obesity and fatty liver through post-transcriptional regulation of numerous genes in multiple cell types. Emerging evidence shows that IGF2BP2 is an N6-methyladenosine (m6A) reader that participates in the development and progression of cancers by communicating with different RNAs such as microRNAs (miRNAs), messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Additionally, IGF2BP2 is an independent prognostic factor for multiple cancer types. In this review, we summarize the current knowledge on IGF2BP2 with regard to diverse human metabolic diseases and its potential for cancer prognosis.

scholarly journals Neddylation Regulates Macrophages and Implications for Cancer Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanyu Jiang ◽  
Lihui Li ◽  
Yan Li ◽  
Guangwei Liu ◽  
Robert M. Hoffman ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cancer Progression ◽  
Therapeutic Strategy ◽  
Cell Types ◽  
Cellular Responses ◽  
Present Review ◽  
Biological Processes ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Multiple Cell

Tumor-associated macrophages (TAMs) promote cancer progression via stimulating angiogenesis, invasion/metastasis, and suppressing anti-cancer immunity. Targeting TAMs is a potential promising cancer therapeutic strategy. Neddylation adds the ubiquitin-like protein NEDD8 to substrates, and thereby regulates diverse biological processes in multiple cell types, including macrophages. By controlling cellular responses, the neddylation pathway regulates the function, migration, survival, and polarization of macrophages. In the present review we summarized how the neddylation pathway modulates Macrophages and its implications for cancer therapy.

scholarly journals Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 840
Author(s):  
Giuseppe Donato ◽  
Ivan Presta ◽  
Biagio Arcidiacono ◽  
Marco F.M. Vismara ◽  
Annalidia Donato ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Adaptive Immune Response ◽  
Cell Types ◽  
Cell Junctions ◽  
Long Distance ◽  
Mesenchymal Transition ◽  
History Of ◽  
Multiple Cell

In the adult, many embryologic processes can be co-opted by during cancer progression. The mechanisms of divisions, migration, and the ability to escape immunity recognition linked to specific embryo antigens are also expressed by malignant cells. In particular, cells derived from neural crests (NC) contribute to the development of multiple cell types including melanocytes, craniofacial cartilage, glia, neurons, peripheral and enteric nervous systems, and the adrenal medulla. This plastic performance is due to an accurate program of gene expression orchestrated with cellular/extracellular signals finalized to regulate long-distance migration, proliferation, differentiation, apoptosis, and survival. During neurulation, prior to initiating their migration, NC cells must undergo an epithelial–mesenchymal transition (EMT) in which they alter their actin cytoskeleton, lose their cell–cell junctions, apicobasal polarity, and acquire a motile phenotype. Similarly, during the development of the tumors derived from neural crests, comprising a heterogeneous group of neoplasms (Neural crest-derived tumors (NCDTs)), a group of genes responsible for the EMT pathway is activated. Here, retracing the molecular pathways performed by pluripotent cells at the boundary between neural and non-neural ectoderm in relation to the natural history of NCDT, points of contact or interposition are highlighted to better explain the intricate interplay between cancer cells and the innate and adaptive immune response.

scholarly journals A framework for mutational signature analysis based on DNA shape parameters

2020 ◽  
Author(s):  
Aleksandra Karolak ◽  
Fran Supek
Keyword(s):  
Dna Repair ◽  
Base Pair ◽  
Mutation Frequency ◽  
Chemical Exposure ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Frequency Spectra ◽  
Radiation Chemical ◽  
Mutational Signature ◽  
Dna Shape

AbstractThe propensity to acquire mutations depends on the oligonucleotide context of a DNA locus. In turn, this differential mutability of oligonucleotides varies across individuals due to exposure to mutagenic agents or due to variable efficiency of DNA repair pathways. Such variability is captured by mutational signatures, mathematical constructs resulting from a deconvolution of mutation frequency spectra across individuals. There is a need to enhance methods for inferring mutational signatures to make better use of sparse mutation frequency data that results from genome sequencing, and additionally to facilitate insight into underlying biological mechanisms. In cancer genomics, novel approaches to analyze somatic mutation patterns may help explain the etiology of various tumor types, as well as provide a more accurate baseline to infer positive and negative selection on somatic changes that drive tumor evolution. We propose a conceptualization of mutational signatures that represents oligonucleotides via descriptors of DNA conformation: base pair, base pair step, and minor groove width parameters. We demonstrate how such DNA structural parameters can accurately predict mutation occurrence due to DNA repair failures or due to exposure to diverse mutagens, including radiation, chemical exposure and the APOBEC cytosine deaminase enzymes. Furthermore, the mutation frequency of DNA oligomers classed by structural features can accurately capture systematic variability in mutational spectra of >1,000 tumors originating from diverse human tissues. Overall, we suggest that the power of DNA sequence-based mutational signature analysis can be enhanced by drawing on DNA shape features.

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