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Le rôle du APC (Anaphase-Promoting Complex) au cours de la phase G2/M après dommage de l’ADN

Year: 2007
Type: dissertation
Abstract: DNA damaging agents are the most widely used treatment in fight against cancer. The effective use of DNA damaging agents for killing tumors depends on understanding the mechanism of DNA damage checkpoint arrest at the molecular level. DNA damage checkpoints impose delays in cell cycle in response to DNA damage. Cells arrest in G2/M after treatment with DNA-damaging agents, such as chemotherapeutic agents and x-rays. In human cells DNA damage checkpoints are of critical importance in carcinogenesis since inactivation of the checkpoint leads to increased rates of mutation, chromosomal loss or aneuploidy. While G-1 arrest after DNA damage has been extensively studied, the mechanism of G2 arrest is less clear. Among the cell cycle checkpoints, G2 is most crucial for preventing entry into mitosis with damaged DNA. We have found a previously unrecognized link between anaphase promoting complex (APC) and G2 checkpoint control after DNA damage. The APC is a large multi-protein complex with E3-ubiquitin ligase activity. APC is best known for regulating progression through mitosis and mitotic exit activity by degradation of various mitotic substrates. APC activity is high from late mitosis until late G-1 phase of the cell cycle. We surprisingly find that APC is activated following DNA damage in cells arrested in G2. DNA damage was induced in synchronized cells in late S phase. Following DNA damage, cells show G2 delay and remain arrested in with a DNA content of 4N. Importantly, we show that down-regulation of APC activity by siRNA technique abolishes G2 checkpoint control after DNA damage. We've analyzed how DNA damage that leads to APC activation. The specific destruction of a regulator by APC may govern cell cycle arrest after DNA damage.
Source: HAL
Author: Lee J
Language: French
Open Access status: green
OpenAlex ID: W112305994
Cites: 46
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Related to: 10