scholarly journals Dynamics of the DNA damage response: insights from live-cell imaging

2013 ◽  
Vol 12 (2) ◽  
pp. 109-117 ◽  
Author(s):  
K. Karanam ◽  
A. Loewer ◽  
G. Lahav
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Live Cell ◽  
Damage Response

scholarly journals Persistence and Dynamics of DNA Damage Signal Amplification Determined by Microcolony Formation and Live-cell Imaging

2011 ◽  
Vol 52 (6) ◽  
pp. 766-774 ◽  
Author(s):  
Yasuyoshi OKA ◽  
Motohiro YAMAUCHI ◽  
Masatoshi SUZUKI ◽  
Shunichi YAMASHITA ◽  
Keiji SUZUKI
Keyword(s):  
Dna Damage ◽  
Signal Amplification ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Live Cell

CBIO-17. A NOVEL ROLE FOR ATR KINASE DETERMINES GLIOBLASTOMA TUMOUR CELL INVASION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi30-vi30
Author(s):  
ross carruthers ◽  
Sarah Derby ◽  
Karen Strathdee ◽  
Anthony Chalmers ◽  
Jim Norman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Invasion ◽  
Tumour Cell ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Live Cell ◽  
Tumour Cell Invasion ◽  
Atr Kinase

Abstract BACKGROUND: Widespread contamination of the brain with malignant cells is a predominant feature of glioblastoma (GBM) and fatal brainstem infiltration is frequently observed at autopsy. Whilst radiotherapy improves survival, irradiation increases GBM cell invasion, resulting in sublethal dose to cells migrating outside the irradiated volume. Tumour cell invasion should be a therapeutic priority if survival is to be improved. The responsible molecular mechanisms are key to improving outcomes but remain enigmatic. Ataxia telangiectasia and rad3-related (ATR) is a DNA damage response (DDR) kinase involved in DNA replication stress (RS) response and is an established therapeutic target for GBM. In this study we demonstrate a novel role for ATR kinase in facilitating malignant cell invasion. METHODS AND RESULTS: Invading margins of human GBM samples demonstrated increased pATR expression relative to core. Live cell imaging demonstrated a reduction in cell velocity following ATR inhibition (ATRi; VE822) or ATR siRNA, and a retraction defect was evident in vitro. Extensive cytoplasmic vacuolation occurred following ATRi or siRNA which were single walled structures on electron microscopy which could engulf high molecular weight dextran, suggesting blockade of macropinosome processing. Live cell imaging with GFP-integrin α5 and integrin recycling assays showed integrin sequestration within macropinosomes and reduced integrin internalisation respectively. Interrogation of a published ‘ATR interactome’ revealed ATR targets with functions in endocytic vesicle trafficking. Intravital in vivo imaging of murine xenograft tumours confirmed vacuolation and dextran uptake following ATRi, whilst a further study demonstrated reduced invading tumour cells following ATRi in intracranial xenografts. CONCLUSION: We demonstrate a novel role for ATR in facilitating macropinocytic vesicle trafficking and integrin internalisation. ATRi results in a profound motility defect in vitro and in vivo. ATR inhibitors are entering early phase trials as radiation sensitisers and we propose that therapeutic benefit will extend beyond DNA damage potentiation.

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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