التفاصيل البيبلوغرافية
| العنوان: |
Deciphering the role of DNA damage response and lysosomal pathways in cell death and senescence induced by a G-quadruplex ligand ; Caractérisation du rôle de la voie de réponse aux dommages à l'ADN et des lysosomes dans la mort cellulaire et la sénescence induites par un ligand G-quadruplexe |
| المؤلفون: |
Beauvarlet, Jennifer |
| المساهمون: |
Bordeaux, Djavaheri-Mergny, Mojgan |
| المصدر: |
Theses.fr |
| سنة النشر: |
2018 |
| مصطلحات موضوعية: |
Ligand G-Quadruplexe, Réponse aux dommages à l'ADN, Lysosome, Mort cellulaire, Sénescence, Cancer, G-Quadruplex ligand, DNA damage response, Cell death, envir, socio |
| الوصف: |
G-quadruplexes (G4) are unusual nucleic acid structures that can be formed by guanine-rich DNA and RNA. Through their ability to stabilize G4 structures, G4 ligands (G4L) have been described to display potent anticancer properties. Here, we studied the G4L 20A belonging to the triarylpyridine family of compounds that have the ability to efficiently bind to and stabilize G4 structures in vitro. The objectives of this work were to determine the molecular and cellular mechanisms responsible for the anti-proliferative effects of 20A in cancer cells. In this study, we showed that 20A causes cancer cell growth arrest in cell culture and a mice tumour xenograft model, through induction of senescence and apoptotic cell death. These cellular responses are associated with the induction of the DNA damage response pathway (DDR), in particular ATM activation, which promotes the induction of both autophagy (a lysosomal catabolic pathway) and senescence, while protecting cells against apoptosis. Furthermore, we found that 20A induces failure of cytokinesis which results in the accumulation of binucleated cells that display marked resistance to 20A-induced cell death. Unexpectedly, we found that 20A accumulates in the lysosomal compartment and causes lysosome enlargement. The combination of a lysosomotropic agent, chloroquine, and 20A promotes a significant induction of lysosomal membrane permeabilization (LMP) and a robust cell death. In particular, this combination significantly sensitizes binucleated cells to cell death. Altogether, our results uncover the relationship of the DDR and lysosomal pathways to cell death and senescence induced by the G4L 20A. Such regulation should also be taken into account when using antiproliferative drugs susceptible to interfere with the lysosomal functions. ; Les G-quadruplexes (G4) sont des structures non canoniques des acides nucléiques qui peuvent être formés dans des régions d’ADN ou d’ARN riches en guanines. Les ligands G4 (LG4), sont des molécules capables d’interagir et de stabiliser ... |
| نوع الوثيقة: |
thesis |
| اللغة: |
French |
| العلاقة: |
10670/1.94f768; http://www.theses.fr/2018BORD0318/documentTest |
| الإتاحة: |
http://www.theses.fr/2018BORD0318/documentTest |
| حقوق: |
other |
| رقم الانضمام: |
edsbas.F63A9A2E |
| قاعدة البيانات: |
BASE |
