scholarly journals Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Mengfei Yao ◽  
Yaqian Wu ◽  
Yanan Cao ◽  
Haijing Liu ◽  
Ningning Ma ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Genomic Dna ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Growth And Survival ◽  
Human Cancer Cells ◽  
Cytoplasmic Dna ◽  
Chemical Inhibitors ◽  
Nuclear Damage

The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.

scholarly journals Autophagy-Mediated Clearance of free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

2021 ◽  
Author(s):  
Mengfei Yao ◽  
Yaqian Wu ◽  
Yanan Cao ◽  
Haijing Liu ◽  
Ningning Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Genomic Dna ◽  
Breast Cancer Cells ◽  
Human Cancer ◽  
Statistical Tests ◽  
P Value ◽  
Growth And Survival ◽  
Selective Autophagy

Abstract Background: The cGAS (GMP-AMP synthase)-triggered senescence-associated secretory phenotype (SASP) in promotion of cancer progression has been extensively documented. However, the role of cGAS-mediated DNA autophagy is little evaluated in cancer cells.Methods: Immunofluorescence, senescence associated-β-galactosidase staining (SA-β-gal) and Western blot were performed to detect gene expression, distribution and phenotypes. PCR, IP-PCR, FISH, BrdU, Comet assay, coimmunoprecipitation, sucrose density gradient centrifugation were carried out to detect possible mechanisms. Trypan blue exclusion, Live/dead staining and MTS assay were to measure the cell viability. All analyses were performed using GraphPad Prism 8. Relationships were analyzed using t-tests. A P-value of less than 0.05 was considered significant. All statistical tests and P values were 2-sided, and the level of significance was set at <0.05 (*), <0.01 (**), <0.001 (***), or<0.0001 (****); ns indicates no significance.Results: Active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cells with high micronucleus (MN). The selective autophagy of free genomic DNA in the cytoplasm is mediated by cGAS and usually coordinated with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA together with nuclear proteins derive from DNA replication-induced nuclear damage and MN collapse. The inhibition of DNA autophagy through either chemical inhibitors or genomic silencing of cGAS or SQSTM1 suppresses the growth and survival of cancer cells, while enhanced DNA damage increases the sensitivity to these inhibitors. Human cancer cells with either high DNA autophagy or enhancement of DNA damage are sensitive to inhibition of DNA autophagy.Conclusions: Our investigation revealed DNA autophagy in breast cancer cells with high MN formation. Autophagy of genomic DNA in the cytosol could be mediated by cGAS but is usually coordinated with other autophagic mediators. The selective autophagy mediated clearance of free genomic DNA protects of growth and survival cancer cells, and autophagic inhibition could be a potential therapeutic approach for cancer cells with high DNA autophagic activity.

scholarly journals Withanolide D Enhances Radiosensitivity of Human Cancer Cells by Inhibiting DNA Damage Non-homologous End Joining Repair Pathway

2020 ◽  
Vol 9 ◽  
Author(s):  
Jerome Lacombe ◽  
Titouan Cretignier ◽  
Laetitia Meli ◽  
E. M. Kithsiri Wijeratne ◽  
Jean-Luc Veuthey ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Repair Pathway ◽  
End Joining ◽  
Human Cancer Cells ◽  
Non Homologous End Joining

scholarly journals Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells

2020 ◽  
Vol 63 (6) ◽  
pp. 3090-3103 ◽  
Author(s):  
Jussara Amato ◽  
Giulia Miglietta ◽  
Rita Morigi ◽  
Nunzia Iaccarino ◽  
Alessandra Locatelli ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Genome Instability ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
G Quadruplex ◽  
Selective Ligands

scholarly journals Detection of repair activity during the DNA damage-induced G2 delay in human cancer cells

Oncogene ◽  
2001 ◽  
Vol 20 (27) ◽  
pp. 3486-3496 ◽  
Author(s):  
Gary D Kao ◽  
W Gillies McKenna ◽  
Tim J Yen
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
Repair Activity ◽  
G2 Delay

Study of the biological effects and DNA damage exerted by a new dipalladium-Hmtpo complex on human cancer cells

2002 ◽  
Vol 90 (1-2) ◽  
pp. 51-60 ◽  
Author(s):  
Khalid Akdi ◽  
Rosario A. Vilaplana ◽  
Sanaa Kamah ◽  
Jorge A.R. Navarro ◽  
Juan M. Salas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Biological Effects ◽  
Human Cancer Cells

Differential response between the p53 ubiquitin–protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells

2006 ◽  
Vol 312 (17) ◽  
pp. 3370-3378 ◽  
Author(s):  
Wenrui Duan ◽  
Li Gao ◽  
Xin Wu ◽  
Yang Zhang ◽  
Gregory A. Otterson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Differential Response ◽  
Human Cancer Cells ◽  
Protein Ligases

scholarly journals The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1161 ◽  
Author(s):  
Magdalena Cal ◽  
Irwin Matyjaszczyk ◽  
Ireneusz Litwin ◽  
Daria Augustyniak ◽  
Rafał Ogórek ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Reactive Oxygen ◽  
Atp Depletion ◽  
Mitochondrial Enzymes ◽  
Oxygen Species ◽  
Human Cancer Cells ◽  
The Impact

3-bromopyruvate (3-BP) is a small molecule with anticancer and antimicrobial activities. 3-BP is taken up selectively by cancer cells’ mono-carboxylate transporters (MCTs), which are highly overexpressed by many cancers. When 3-BP enters cancer cells it inactivates several glycolytic and mitochondrial enzymes, leading to ATP depletion and the generation of reactive oxygen species. While mechanisms of 3-BP uptake and its influence on cell metabolism are well understood, the impact of 3-BP at certain concentrations on DNA integrity has never been investigated in detail. Here we have collected several lines of evidence suggesting that 3-BP induces DNA damage probably as a result of ROS generation, in both yeast and human cancer cells, when its concentration is sufficiently low and most cells are still viable. We also demonstrate that in yeast 3-BP treatment leads to generation of DNA double-strand breaks only in S-phase of the cell cycle, possibly as a result of oxidative DNA damage. This leads to DNA damage, checkpoint activation and focal accumulation of the DNA response proteins. Interestingly, in human cancer cells exposure to 3-BP also induces DNA breaks that trigger H2A.X phosphorylation. Our current data shed new light on the mechanisms by which a sufficiently low concentration of 3-BP can induce cytotoxicity at the DNA level, a finding that might be important for the future design of anticancer therapies.

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