Faculty Opinions recommendation of Cotranscriptional exon skipping in the genotoxic stress response.

p53 is recruited in response to DNA-damaging genotoxic stress and plays an important role in maintaining the integrity of the genome. We show that exposure of cells to various genotoxic agents, including anticancer drugs such as mitomycin and 5-fluorouracil, results in an increase in p53 mRNA levels and in p53 promoter activation, indicating that the p53 genotoxic stress response is partly regulated at the transcriptional level. The results of the p53 promoter analysis show that a novel p53 promoter element, termed a p53 core promoter element (from -70 to -46), is essential for basal p53 promoter activity and promoter activation induced by genotoxic agents such as anticancer drugs and UV. Although a kappa B motif partially overlaps with this element and those genotoxic agents activate NF-kappa B, it does not play a major role in p53 genotoxic stress response: NF-kappa B p65 expression did not induce significant p53 promoter activation, and NF-kappa B inhibitors (N-acetyl cysteine and I kappa B alpha) did not inhibit genotoxic stress-inducible p53 promoter activation. Finally, we characterized nuclear factors, the binding of which to the p53 core promoter element is essential for basal p53 promoter activity and p53 promoter activation induced by genotoxic agents.

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Genotoxic Stress Response Gene Expression in the Mid-Organogenesis Rat Conceptus

Toxicological Sciences ◽

10.1093/toxsci/kfg097 ◽

2003 ◽

Vol 74 (1) ◽

pp. 157-164 ◽

Cited By ~ 11

Author(s):

R. K. Vinson

Keyword(s):

Gene Expression ◽

Stress Response ◽

Genotoxic Stress ◽

Response Gene ◽

Stress Response Gene

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The mRNA Surveillance Protein hSMG-1 Functions in Genotoxic Stress Response Pathways in Mammalian Cells

Molecular Cell ◽

10.1016/j.molcel.2004.05.005 ◽

2004 ◽

Vol 14 (5) ◽

pp. 585-598 ◽

Cited By ~ 146

Author(s):

Kathryn M. Brumbaugh ◽

Diane M. Otterness ◽

Christoph Geisen ◽

Vasco Oliveira ◽

John Brognard ◽

...

Keyword(s):

Stress Response ◽

Mammalian Cells ◽

Genotoxic Stress ◽

Mrna Surveillance

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Author Correction: Proteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response

Nature Communications ◽

10.1038/s41467-021-26886-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yubo Liu ◽

Qiushi Chen ◽

Nana Zhang ◽

Keren Zhang ◽

Tongyi Dou ◽

...

Keyword(s):

Stress Response ◽

Genotoxic Stress ◽

Proteomic Profiling ◽

Genome Wide ◽

Associated Proteins

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Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

10.1101/847996 ◽

2019 ◽

Cited By ~ 1

Author(s):

David R. Amici ◽

Jasen M. Jackson ◽

Kyle A. Metz ◽

Daniel J. Ansel ◽

Roger S. Smith ◽

...

Keyword(s):

Stress Response ◽

Biological Networks ◽

Genotoxic Stress ◽

Cellular Stress Response ◽

Genetic Screens ◽

Master Regulators ◽

Functional Relationships ◽

Response Network ◽

The Face ◽

Genome Scale

SummaryThe interrelated programs essential for cellular fitness in the face of stress are critical to understanding tumorigenesis, neurodegeneration, and aging. However, modelling the combinatorial landscape of stresses experienced by diseased cells is challenging, leaving functional relationships within the global stress response network incompletely understood. Here, we leverage genome-scale fitness screening data from 625 cancer cell lines, each representing a unique biological context, to build a network of “coessential” gene relationships centered around master regulators of the response to proteotoxic, oxidative, hypoxic, and genotoxic stress. This approach organizes the stress response into functional modules, identifies genes connecting distinct modules, and reveals mechanisms underlying cellular dependence on individual modules. As an example of the power of this approach, we discover that the previously unannotated HAPSTR (C16orf72) promotes resilience to diverse stressors as a stress-inducible regulator of the E3 ligase HUWE1. Altogether, we present a broadly applicable framework and interactive tool (http://fireworks.mendillolab.org/) to interrogate biological networks using unbiased genetic screens.

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ABL1 Methylation Is a Distinct Molecular Event Associated With Clonal Evolution of Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v94.7.2452.419k23_2452_2460 ◽

1999 ◽

Vol 94 (7) ◽

pp. 2452-2460 ◽

Cited By ~ 69

Author(s):

Fotis A. Asimakopoulos ◽

Pesach J. Shteper ◽

Svetlana Krichevsky ◽

Eitan Fibach ◽

Aaron Polliack ◽

...

Keyword(s):

Dna Repair ◽

Stress Response ◽

Chronic Myeloid Leukemia ◽

Cell Lines ◽

Myeloid Leukemia ◽

Blast Crisis ◽

Clonal Evolution ◽

Genotoxic Stress ◽

Clinical Samples ◽

Hematopoietic Progenitors

Methylation of the proximal promoter of the ABL1 oncogene is a common epigenetic alteration associated with clinical progression of chronic myeloid leukemia (CML). In this study we queried whether both the Ph′-associated and normal ABL1 alleles undergo methylation; what may be the proportion of hematopoietic progenitors bearing methylated ABL1 promoters in chronic versus acute phase disease; whether methylation affects the promoter uniformly or in patches with discrete clinical relevance; and, finally, whether methylation of ABL1 reflects a generalized process or is gene-specific. To address these issues, we adapted the techniques of methylation-specific PCR and bisulfite-sequencing to study the regulatory regions of ABL1 and other genes with a role in DNA repair or genotoxic stress response. In cell lines established from CML blast crisis, which only carry a single ABL1 allele nested within the BCR-ABL fusion gene, ABL1 promoters were universally methylated. By contrast, in clinical samples from patients at advanced stages of disease, both methylated and unmethylated promoter alleles were detectable. To distinguish between allele-specific methylation and a mixed cell population pattern, we studied the methylation status of ABL1 in colonies derived from single hematopoietic progenitors. Our results showed that both methylated and unmethylated promoter alleles coexisted in the same colony. Furthermore, ABL1 methylation was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML. Both cell lines and clinical samples from acute-phase CML showed nearly uniform hypermethylation along the promoter region. Finally, we showed that ABL1 methylation does not reflect a generalized process and may be unique among DNA repair/genotoxic stress response genes. Our data suggest that specific methylation of the Ph′-associatedABL1 allele accompanies clonal evolution in CML.

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