Drosophila Checkpoint Kinase 2 Couples Centrosome Function and Spindle Assembly to Genomic Integrity

Abstract

In syncytial Drosophila embryos, damaged or incompletely replicated DNA triggers centrosome disruption in mitosis, leading to defects in spindle assembly and anaphase chromosome segregation. The damaged nuclei drop from the cortex and are not incorporated into the cells that form the embryo proper. A null mutation in the Drosophila checkpoint kinase 2 tumor suppressor homolog (DmChk2) blocks this mitotic response to DNA lesions and also prevents loss of defective nuclei from the cortex. In addition, DNA damage leads to increased DmChk2 localization to the centrosome and spindle microtubules. DmChk2 is therefore essential for a "mitotic catastrophe" signal that disrupts centrosome function in response to genotoxic stress and ensures that mutant and aneuploid nuclei are eliminated from the embryonic precursor pool.

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

“…An increasing number of reports also discuss the potential compartmentalisation of proteins in the context of DNA damage responses Löffer et al, 2006). Centrosomes are becoming key structures of interest, containing an abundance of mitotic control and DNA damage response factors (Takada et al, 2003;Löffer et al, 2006;Jackman et al, 2003;Golsteyn et al, 1995;Tsvetkov et al, 2003). This thesis shows evidence correlating with previous investigations in other systems, in which centrosomes were inactivated as the end-result of DNA damage induced pathways in mitosis (Sibon et al, 2000;Sibon, 2003;Takada et al, 2003;Löffer et al, 2006).…”

“…Centrosomes are becoming key structures of interest, containing an abundance of mitotic control and DNA damage response factors (Takada et al, 2003;Löffer et al, 2006;Jackman et al, 2003;Golsteyn et al, 1995;Tsvetkov et al, 2003). This thesis shows evidence correlating with previous investigations in other systems, in which centrosomes were inactivated as the end-result of DNA damage induced pathways in mitosis (Sibon et al, 2000;Sibon, 2003;Takada et al, 2003;Löffer et al, 2006). Furthermore, it is possible that the control of CEP63 centrosome function by ATM and ATR could potentially participate in preventing genomic instability and cellular transformations, in which centrosomes role has been proven (Basto et al, 2008).…”

“…In this situation centrosome inactivation occurs after checkpoint failure in response to DNA damage at the point of mitosis onset. These findings were followed by another study in Drosophila embryos, which showed Chk2 dependent destruction of centrosome function induced by the presence of DNA damage (Takada et al, 2003). It is generally thought that defective mitotic cells undergo mitotic catastrophe, which in turn leads to their elimination from the cell population by cell death (Schatten et al, 1999;Roninson et al, 2001).…”

Réponse aux dommages à l’ADN durant l’embryogenèse

“…En résumé, cette étude récente a permis d'établir un lien inattendu entre le méta-ainsi expliquer, par exemple, l'origine de la perturbation de l'expression de protéines centrosomales en présence de dommages à l'ADN [7,8]. Afin de comprendre plus en détail le mécanisme moléculaire modulant la rétention nucléaire des ARNm induite par Chk2, nous avons focalisé notre attention sur un groupe bien particulier de transcrits, qui codent pour les protéines d'histones.…”

“…De plus, les auteurs ont souligné l'implication dans ce processus de la kinase Chk2, encodée par le gène mnk (maternal nuclear kinase) chez la drosophile. En effet, les embryons mutants pour mnk sont incapables d'induire l'élimination de noyaux défectueux et accumulent des agrégats nucléaires anormaux dans l'épithélium embryonnaire [7,9]. Cependant, les mécanismes moléculaires par lesquels Chk2 module le triage nucléaire et l'inactivation des centrosomes restaient toujours énigmatiques.…”