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Modulation of the ATM/autophagy pathway tips the balance between senescence and apoptosis in response to 20A ligand

ABSTRACT: Modulation of the ATM/autophagy pathway tips the balance between senescence and apoptosis in response to 20A ligand

PROVIDER: PRJNA451127 | ENA |

REPOSITORIES: ENA

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Modulation of the ATM/autophagy pathway tips the balance between senescence and apoptosis in response to 20A ligand

Project description:G-quadruplex ligands (G4L) exert their anti-proliferative effect through telomere-dependent and -independent mechanisms, but the inter-relationship between autophagy, cell growth arrest and cell death induced by these ligands remains largely unexplored. 20A is a 2,4,6-triarylpyridine derivative that binds to G4-DNA with fair to excellent selectivity. Here, we demonstrate that this compound impairs cancer cell viability through induction of senescence and apoptotic cell death in a p53-independent manner. In vivo results corroborate those obtained in in vitro, showing that 20A elicits an important tumor growth inhibition in HeLa-xenografted tumor model. The transcriptomic and proteomic analyses reveal the functional enrichment in the growth arrest, DDR and lysosomal pathways upon 20A treatment. More particularly, we find that ATM and autophagy are activated upon 20A treatment. Genetic inhibition of ATM following 20A treatment inhibits both autophagy and senescence and directs cells to apoptosis. Moreover, loss of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation and increased cell death triggered by 20A. Our results therefore identify ATM as a critical determinant in the balance between senescence and apoptosis and uncover autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal therapeutic effect of the 20A G4-ligand.

2019-04-17 | GSE113424 | GEO

Modulation of the ATM / autophagy pathway tips the balance between senescence and apoptosis in response to a quadruplex ligand

2019-02-19 | PXD009430 | Pride

ATM keypad - molecular cartography

Project description:LC-MS/MS data from swab sampling of ATM keypad buttons and finger tips of a person who typed a four-digit PIN.

2017-02-22 | MSV000080560 | MassIVE

Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells.

Project description:G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.

| S-EPMC6451122 | biostudies-literature

Pseudomonas parafulva strain:20a

Project description:Pseudomonas parafulva 20a genome sequencing

| PRJNA442837 | ENA

QK-knockdown U87 transduced with miR-20a or a scrambled non-targeting microRNA (miR-NT)

Project description:Identify potential miR-20a regulated mRNAs and linked pathways in the setting of QK knockdown by comparing the transcriptional profiles of shQK-transduced human U87 cells together with miR-20a or a scrambled miRNA control (miR-NT)

2009-12-30 | GSE19690 | GEO

QK-knockdown Hs683 transduced with miR-20a or a scrambled non-targeting microRNA (miR-NT)

Project description:Identify potential miR-20a regulated mRNAs and linked pathways in the setting of QK knockdown by comparing the transcriptional profiles of shQK-transduced human Hs683 cells together with miR-20a or a scrambled miRNA control (miR-NT)

2009-12-30 | GSE19688 | GEO

Panicum virgatum strain:ATM | cultivar:ATM

Project description:Panicum virgatum ATM Resequencing genome sequencing

| PRJNA332580 | ENA

A global transcriptome analysis of human epidermal keratinocytes upon overexpression of microRNA-19a or microRNA-19b or microRNA-20a

Project description:Several members from microRNA 17-92 cluster, i.e. miR-19a, miR-19b and miR-20a, were found up-regulated in human epidermal keratinocytes at wound-edges compared to the intact skin; however their biological role in keratinocytes during wound repair has not been studied. To study the genes regulated by miR-19a, miR-19b and miR-20a, we transfected miRNA specific mimics, i.e. pre-miR-19a, pre-miR-19b or pre-miR-20a into human primary epidermal keratinocytes to overexpress them. We performed a global transcriptome analysis of keratinocytes upon overexpression of miR-19a or miR-19b or miR-20a using Affymetrix arrays.

2017-02-15 | GSE93110 | GEO

QK-knockdown Ink4a/Arf-/- Pten-/- mouse astrocytes transduced with miR-20a or scrambled non-targeting microRNA (miR-NT)

Project description:Identify potential miR-20a regulated mRNAs and linked pathways in the setting of QK knockdown by comparing the transcriptional profiles of shQK-transduced primary mouse Ink4a/Arf-/- Pten-/- astrocytes together with miR-20a or a scrambled miRNA control (miR-NT)

2009-12-30 | GSE19689 | GEO

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