centrosomes in checkpoint responses
TRANSCRIPT
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Cell Cycle
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Checkpoints
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Centrosomes
Definition• A single mammalian centrosome
comprises two centrioles, embedded in a protein meshwork known as the pericentriolar material.
• Centrioles are cylindrical organelles made up of triplet microtubules.
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Centrosomes
Functions• Regulation of the G2/M transition in response to DNA damage
• Induction of cell death via centrosome amplification and mitotic catastrophe as a backup mechanism for the elimination of cells that evade DNA damage checkpoints operating earlier during the cell cycle.
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Centrosome reproduction cycle
• Centrosome duplication occurring during S phase and
centrosome segregation during M phase
• cells in G1 phase of the cell cycle contain
a single centrosome consisting of one older
or mature and one younger or daughter centriole.
• a G2 phase cell harbors two
centrosomes, each comprising two
closely linked centrioles.
• in M phase the two centrioles of every centrosome are
separated from each other in a process termed disengagement.
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Centrosome\DNA Replication Regulators
• Both centrosome and DNA replication are initiated by the activation of cyclin dependent kinase 2 (Cdk2), in association with cyclins E and/or A in late G1 phase of the cell cycle.
• polo-like kinase 4 (Plk4) has unequivocally been identified as a positive regulator of centriole duplication. overexpression of Plk4 in human cells results in the production of multiple
centriole precursors surrounding a single parental centriole and Plk4+/− mice are prone to develop tumors
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Centrosomal Regulation of the G2/M Transition
• Centrosomal Regulation of Unperturbed G2/M Progression Cdc25 Aurora-A Chk1
• Centrosomal Regulation of the DNA-Damage-Induced G2/M Checkpoint DNA Damage Checkpoint Network Role of Centrosomes
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Centrosomal Regulation of Unperturbed G2/M Progression
Cdk1Cdc25
Dephosphorylation
Aurora-A
Phosphorylation
AjubaActivatin
Cyclin B
Chk1
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Centrosomal Regulation of the DNA-Damage-Induced G2/M Checkpoint
• The DNA damage checkpoint network DNA damage sensors Signal transducers Various effector pathways Central components are the phosphoinositide 3-kinase related kinases ATM
and ATR (which relay their signals to the downstream checkpoint kinases Chk1 and Chk2).
ATM is activated primarily by DNA double strand breaks induced by ionizing radiation, whereas ATR also responds to ultraviolet (UV) radiation or stalled replication forks. While ATM predominantly phosphorylates Chk2, ATR is required for Chk1 phosphorylation after exposure to UV or replicative stress.
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• Role of centrosomes
Chk1 is central protein in Centrosomal Regulation of the DNA-Damage-Induced G2/M Checkpoint.
Upon activation of the G2/M checkpoint by DNA damage, activating phosphorylation of centrosomal Cdc25 does not occur.
Chemical inhibition of Chk1 does not only abrogate the G2/M checkpoint but has been shown to induce centrosomal Aurora-A activation as evidenced by phosphorylation and subsequent Cdc25 activation via phosphorylation, implying that centrosomal Aurora-A kinase activity is directly or indirectly controlled by Chk1 following DNA damage.
Centrosomal Regulation of the DNA-Damage-Induced G2/M Checkpoint
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DNA-Damage-Induced Centrosome Amplification
• Centrosome amplification has been frequently observed in both solid tumors and hematological malignancies and is linked to aneuploidy and tumorigenesis.
• Centrosome amplification may lead to chromosomal instability and/or mitotic catastrophe through the formation of multipolar mitotic spindles resulting in chromosome missegregation.
• Impaired homologous recombination causes deleterious genetic rearrangements, which could have a causative role in malignant transformation; loss or inactivation of homologous recombination repair proteins results in centrosome amplification.
• Overexpression of the DNA damage sensor ATR and its downstream transducer Chk1 lead to centrosome amplification
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Centrosome amplification mechanisms
• Overreplication of centrosomes within a single cell cycle
• a cell division/cytokinesis defect associated with amplification of both centrosomes and cellular DNA content.
• In the absence of DNA damage, tetraploidization has been proposed as a major route to centrosome amplification.
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