DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos

Sibon, Ody C. M.; Kelkar, Anju; Lemstra, Willy; Theurkauf, William E.

doi:10.1038/35000041

Cited by 140 publications

(153 citation statements)

References 33 publications

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“…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).…”

Section: Atm and Atr Inhibition Of Xcep63 Regulatory Role In Spindle supporting

confidence: 68%

“…Originally, a report by Sibon et al, showed that unreplicated DNA or incorporation of DNA damage can induce the loss of centrosome function in Drosophila embryos in mitosis. This loss of centrosome function was associated with the displacement of -TuRCs, which led to the formation of insufficient spindle structures that were unable to segregate chromosomes (Sibon et al, 2000). In this situation centrosome inactivation occurs after checkpoint failure in response to DNA damage at the point of mitosis onset.…”

Section: Growing Evidence Of Centrosomal Checkpoints Responding To Dnmentioning

confidence: 99%

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

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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Section: Atm and Atr Inhibition Of Xcep63 Regulatory Role In Spindle supporting

confidence: 68%

Section: Growing Evidence Of Centrosomal Checkpoints Responding To Dnmentioning

confidence: 99%

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

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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“…If centrosomes are experimentally ablated, somatic cells can still form mitotic spindles, but half of the cells fail to complete a normal cytokinesis and arrest in the G 1 -phase [37,44,45]. In Drosophila, defects in DNA are relayed to the centrosome leading to centrosomal and spindle abnormalities, which are hypothesized to be part of a checkpoint for culling of damaged nuclei [46]. Furthermore, centrosomal abnormalities in cancer cells have been frequently observed [47][48][49][50][51].…”

Section: Introductionmentioning

confidence: 99%

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest

Don

Dallapiazza

Bennin

et al. 2006

Experimental Cell Research

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Cyclin G2 is an atypical cyclin that associates with active protein phosphatase 2A. Cyclin G2 gene expression correlates with cell cycle inhibition; it is significantly upregulated in response to DNA damage and diverse growth inhibitory stimuli, but repressed by mitogenic signals. Ectopic expression of cyclin G2 promotes cell cycle arrest, cyclin dependent kinase 2 inhibition, and the formation of aberrant nuclei [1]. Here we report that endogenous cyclin G2 copurifies with centrosomes and microtubules (MT), and that ectopic G2 expression alters microtubule stability. We find exogenous and endogenous cyclin G2 present at microtubule organizing centers (MTOCs) where it colocalizes with centrosomal markers in a variety of cell lines. We previously reported that cyclin G2 forms complexes with active protein phosphatase 2A (PP2A) and colocalizes with PP2A in a detergent resistant compartment. We now show that cyclin G2 and PP2A colocalize at MTOCs in transfected cells, and that the endogenous proteins copurify with isolated centrosomes. Displacement of the endogenous centrosomal scaffolding protein AKAP450 that anchors PP2A at the centrosome, resulted in the depletion of centrosomal cyclin G2. We find that ectopic expression of cyclin G2 induces microtubule bundling and resistance to depolymerization, inhibition of polymer regrowth from MTOCs, and a p53 dependent cell cycle arrest. Furthermore, we determined that a 100 amino acid carboxy-terminal region of cyclin G2 is sufficient to both direct GFP localization to centrosomes and induce cell cycle inhibition. Colocalization of endogenous cyclin G2 with only one of two GFPcentrin tagged centrioles, the mature centriole present at microtubule foci, indicate that cyclin G2 resides primarily on the mother centriole. Copurification of cyclin G2 and PP2A subunits with microtubules and centrosomes, together with the effects of ectopic cyclin G2 on cell cycle progression, nuclear morphology, and microtubule growth and stability, suggests that cyclin G2 may modulate the cell cycle and cellular division processes through modulation of PP2A and centrosomal associated activities.

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“…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.…”

Section: Resultsunclassified

“…L'épithélium embryonnaire ainsi formé contiendra environ 6 000 cellules progé-nitrices nécessaires à la formation des tissus somatiques de l'adulte [5]. Or, il a précédemment été démontré qu'en réponse à différents stress génotoxiques subis durant les cycles mitotiques 10 à 13, un processus de triage sera enclenché afin d'induire la chute des noyaux endommagés vers le cytoplasme central de l'embryon, où ils seront détruits [6, dGrip85, suggérant ainsi que la perturbation de l'activité normale de cet organite pourrait faciliter l'élimination des noyaux associés [8]. 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.…”

unclassified

Réponse aux dommages à l’ADN durant l’embryogenèse

Iampietro

Lécuyer

2014

Med Sci (Paris)

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DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos

Cited by 140 publications

References 33 publications

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

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

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest

Réponse aux dommages à l’ADN durant l’embryogenèse

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