cell stress response
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Annals of the New York Academy of Sciences, ISSN 0077-8923 Volume 771, Issue 1, December 1995
xviii, 755 s. : obr., tab., grafy ; 24 cm
- MeSH
- buněčná imunita patofyziologie MeSH
- fyziologický stres patofyziologie MeSH
- neuroendokrinologie MeSH
- Publikační typ
- kongresy MeSH
- sborníky MeSH
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- fyziologie
- patologie
- neurovědy
Autophagy is an evolutionarily conserved process that captures aberrant intracellular proteins and/or damaged organelles for delivery to lysosomes, with implications for cellular and organismal homeostasis, aging and diverse pathologies, including cancer. During cancer development, autophagy may play both tumour-supporting and tumour-suppressing roles. Any relationships of autophagy to the established oncogene-induced replication stress (RS) and the ensuing DNA damage response (DDR)-mediated anti-cancer barrier in early tumorigenesis remain to be elucidated. Here, assessing potential links between autophagy, RS and DDR, we found that autophagy is enhanced in both early and advanced stages of human urinary bladder and prostate tumorigenesis. Furthermore, a high-content, single-cell-level microscopy analysis of human cellular models exposed to diverse genotoxic insults showed that autophagy is enhanced in cells that experienced robust DNA damage, independently of the cell-cycle position. Oncogene- and drug-induced RS triggered first DDR and later autophagy. Unexpectedly, genetic inactivation of autophagy resulted in RS, despite cellular retention of functional mitochondria and normal ROS levels. Moreover, recovery from experimentally induced RS required autophagy to support DNA synthesis. Consistently, RS due to the absence of autophagy could be partly alleviated by exogenous supply of deoxynucleosides. Our results highlight the importance of autophagy for DNA synthesis, suggesting that autophagy may support cancer progression, at least in part, by facilitating tumour cell survival and fitness under replication stress, a feature shared by most malignancies. These findings have implications for better understanding of the role of autophagy in tumorigenesis, as well as for attempts to manipulate autophagy as an anti-tumour therapeutic strategy.
- MeSH
- autofagie * MeSH
- autofagozomy účinky léků metabolismus MeSH
- biologické modely MeSH
- fyziologický stres * účinky léků MeSH
- kamptothecin farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- onkogeny * MeSH
- replikace DNA * účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- fyziologický stres metabolismus MeSH
- katecholaminy metabolismus MeSH
- lidé MeSH
- lymfocyty imunologie MeSH
- Check Tag
- lidé MeSH
ATR controls chromosome integrity and chromatin dynamics. We have previously shown that yeast Mec1/ATR promotes chromatin detachment from the nuclear envelope to counteract aberrant topological transitions during DNA replication. Here, we provide evidence that ATR activity at the nuclear envelope responds to mechanical stress. Human ATR associates with the nuclear envelope during S phase and prophase, and both osmotic stress and mechanical stretching relocalize ATR to nuclear membranes throughout the cell cycle. The ATR-mediated mechanical response occurs within the range of physiological forces, is reversible, and is independent of DNA damage signaling. ATR-defective cells exhibit aberrant chromatin condensation and nuclear envelope breakdown. We propose that mechanical forces derived from chromosome dynamics and torsional stress on nuclear membranes activate ATR to modulate nuclear envelope plasticity and chromatin association to the nuclear envelope, thus enabling cells to cope with the mechanical strain imposed by these molecular processes.
- MeSH
- ATM protein metabolismus MeSH
- buňky NIH 3T3 MeSH
- chromatin metabolismus MeSH
- fibroblasty cytologie metabolismus MeSH
- HeLa buňky MeSH
- jaderný obal metabolismus MeSH
- kontrolní body buněčného cyklu MeSH
- lidé MeSH
- mechanický stres * MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- osmóza MeSH
- proteinkinasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
