Differential effect of hypoxia on etoposide-induced DNA damage response and p53 regulation in different cell types

2013 ◽  
Vol 228 (12) ◽  
pp. 2365-2376 ◽  
Author(s):  
Audrey Sermeus ◽  
Magali Rebucci ◽  
Maude Fransolet ◽  
Lionel Flamant ◽  
Déborah Desmet ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Differential Effect ◽  
Cell Types ◽  
Damage Response ◽  
Different Cell Types

scholarly journals TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1186 ◽  
Author(s):  
Sandra Pisonero-Vaquero ◽  
Chiara Soldati ◽  
Marcella Cesana ◽  
Andrea Ballabio ◽  
Diego Luis Medina
Keyword(s):  
Dna Damage ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Cell Types ◽  
Dependent Manner ◽  
Cancer Cell Growth ◽  
Direct Role ◽  
Growth And Survival ◽  
Damage Response ◽  
P21 Waf1

The MiT/TFE family of transcription factors (MITF, TFE3, and TFEB), which control transcriptional programs for autophagy and lysosome biogenesis have emerged as regulators of energy metabolism in cancer. Thus, their activation increases lysosomal catabolic function to sustain cancer cell growth and survival in stress conditions. Here, we found that TFEB depletion dramatically reduces basal expression levels of the cyclin-dependent kinase (CDK) inhibitor p21/WAF1 in various cell types. Conversely, TFEB overexpression increases p21 in a p53-dependent manner. Furthermore, induction of DNA damage using doxorubicin induces TFEB-mediated activation of p21, delays G2/M phase arrest, and promotes cell survival. Pharmacological inhibition of p21, instead, abrogates TFEB-mediated protection during the DNA damage response. Together, our findings uncover a novel and direct role of TFEB in the regulation of p21 expression in both steady-state conditions and during the induction of DNA-damage response (DDR). Our observations might open novel therapeutic strategies to promote cancer cell death by targeting the TFEB-p21 pathway in the presence of genotoxic agents.

The Telomerase Inhibitor RHPS4 Induces Telomere Shortening, DNA-Damage and Cell Death in AML Cells and Chemosensitises Cells to Daunorubicin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2760-2760
Author(s):  
Monica Pallis ◽  
Dotun Ojo ◽  
Jaineeta Richardson ◽  
John Ronan ◽  
Malcolm Stevens ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Telomere Length ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cell Types ◽  
Telomere Shortening ◽  
Damage Response

Abstract Abstract 2760 Poster Board II-736 The quadruplex ligand RHPS4 is the lead compound in a drug discovery program at the University of Nottingham. It has been shown to bind to telomeres and inhibit telomerase, and subsequently induces growth arrest in progenitor cells from cancer cell lines whilst sparing normal haematopoietic progenitor cells. We explored its in vitro effects in AML cells, which are reported generally to have considerably shorter telomeres than normal CD34+ cells. AML cell lines were grown for 21 days in suspension culture. Primary samples were cultured for 14 days in semi-solid medium. Telomere length was measured by Southern blotting. γH2A.X was used to identify a DNA damage response, and cell viability was measured flow cytometrically with 7-amino actinomycin D. As reported in other tumour cell types, sensitivity to RHPS4 was found to be greatest in those AML cells with the shortest telomeres. In the OCI-AML3 cell line 0.3 μM RHPS4 inhibited cell growth by 50% in a 21 day clonogenic assay, accompanied by shortening of telomeres from 2.6 Kb to <1 Kb. Molm 13 cells (initial telomere length 3.2kB) also underwent telomere shortening in the presence of 0.3 μM RHPS4 (2.8Kb), whereas TF1a and U937 (both with initial telomere lengths approximately 6.5 kB) were insensitive at that concentration. After 6 days at 0.3 μM, RHPS4 was cytostatic, but at higher concentrations (1 μM) the drug was found to induce a substantial DNA damage response and loss of viability to OCI-AML3 cells. Moreover 0.3 μM RHPS4 enhanced the γH2A.X expression and cell death induced by the chemotherapy drug daunorubicin in these cells. Using 14 day clonogenic assays in primary AML samples (n=6), we found that the IC50 for RHPS4 alone was 0.7 μM. However, in the presence of 0.3 μM RHPS4, the median IC50 to daunorubicin was reduced from 19 nM to 5.5 nM. In conclusion we have determined that RHPS4 has telomere-shortening, cytostatic, cytotoxic and chemosensitising properties in AML cells. Disclosures: Stevens: Pharminox Ltd: director and shareholder of Pharminox Ltd which has a financial interest in RHPS4.

scholarly journals Mechanisms and Regulation of Cellular Senescence

2021 ◽  
Vol 22 (23) ◽  
pp. 13173
Author(s):  
Lauréline Roger ◽  
Fanny Tomas ◽  
Véronique Gire
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Cell Types ◽  
Feedback Loops ◽  
Cellular Structures ◽  
Damage Response ◽  
Different Types ◽  
Secretory Phenotype ◽  
Different Cell Types ◽  
Different Tissues

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.

scholarly journals Analysis of DNA breaks, DNA damage response, and apoptosis produced by high NaCl

2008 ◽  
Vol 295 (6) ◽  
pp. F1678-F1688 ◽  
Author(s):  
Natalia I. Dmitrieva ◽  
Maurice B. Burg
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Hela Cells ◽  
Cell Types ◽  
Dna Breaks ◽  
Main Subject ◽  
Mrn Complex ◽  
Damage Response

We previously reported that, both in cell culture and in the renal inner medulla in vivo, elevating NaCl increased the number of DNA breaks, which persisted as long as NaCl remained high but were rapidly repaired when NaCl was lowered. Furthermore, those breaks did not induce the DNA repair protein γH2AX or cause activation of the MRN (Mre11, Rad50, Nbs1) complex. In contrast, others recently reported that high NaCl does induce γH2AX and MRN complex formation and concluded that these activities are associated with repair of the DNA (Sheen MR, Kim SW, Jung JY, Ahn JY, Rhee JG, Kwon HM, Woo SK. Am J Physiol Renal Physiol 291: F1014–F1020, 2006). The purpose of the present studies was to resolve the disparity. The important difference is that HeLa cells, which were the main subject of the later report, are much less tolerant of high NaCl than are the mIMCD3 cells, which were our main subject. mIMCD3 cells survive levels of NaCl that kill HeLa cells by apoptosis. Here we demonstrate that in both cell types raising NaCl to a level that the cells survive (higher for mIMCD3 than HeLa) increases DNA breaks without inducing γH2AX or activating the MRN complex and that the DNA breaks persist as long as NaCl remains elevated, but are rapidly repaired when it is lowered. Importantly, in both cell types, raising NaCl further to cause apoptosis activates these DNA damage response proteins and greatly fragments DNA, associated with cell death. We conclude that γH2AX induction and MRN activation in response to high NaCl are associated with apoptosis, not DNA repair.

scholarly journals The DNA Damage Response and HIV-Associated Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (9) ◽  
pp. 3305
Author(s):  
Ari Simenauer ◽  
Eva Nozik-Grayck ◽  
Adela Cota-Gomez
Keyword(s):  
Dna Damage ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dna Damage Response ◽  
Regulatory Networks ◽  
Cell Types ◽  
Pulmonary Vasculature ◽  
Increased Risk ◽  
Damage Response ◽  
Pulmonary Arterial

The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.

2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2118-P
Author(s):  
CHAY TENG YEO ◽  
BRYNDON OLESON ◽  
JOHN A. CORBETT ◽  
JAMIE K. SCHNUCK
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Damage Response
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