Abstract
Defects in chromosome-microtubule attachment trigger spindle-checkpoint activation and delay mitotic progression. How microtubule attachment is sensed and integrated into the steps of checkpoint-signal amplification is poorly understood. In a functional genomic screen targeting human kinases and phosphatases, we identified a microtubule affinity-regulating kinase kinase, TAO1 (also known as MARKK) as an important regulator of mitotic progression, required for both chromosome congression and checkpoint-induced anaphase delay. TAO1 interacts with the checkpoint kinase BubR1 and promotes enrichment of the checkpoint protein Mad2 at sites of defective attachment, providing evidence for a regulatory step that precedes the proposed Mad2-Mad1 dependent checkpoint-signal amplification step. We propose that the dual functions of TAO1 in regulating microtubule dynamics and checkpoint signalling may help to coordinate the establishment and monitoring of correct congression of chromosomes, thereby protecting genomic stability in human cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antimitotic Agents / pharmacology
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Calcium-Binding Proteins / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Chromosome Segregation* / drug effects
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Gene Library
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Genomic Instability
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Genomics / methods
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HeLa Cells
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Humans
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Kinetochores / metabolism
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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Mad2 Proteins
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Mitosis / drug effects
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Mitosis / physiology*
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Mutation
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Nocodazole / pharmacology
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Paclitaxel / pharmacology
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases
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RNA Interference
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Repressor Proteins / metabolism
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Reproducibility of Results
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Signal Transduction* / drug effects
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Spindle Apparatus / drug effects
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Spindle Apparatus / metabolism*
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Time Factors
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Transfection
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Tubulin Modulators / pharmacology
Substances
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Antimitotic Agents
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Calcium-Binding Proteins
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Cell Cycle Proteins
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MAD2L1 protein, human
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Mad2 Proteins
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Repressor Proteins
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Tubulin Modulators
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Protein Kinases
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BUB1 protein, human
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Bub1 spindle checkpoint protein
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Protein Serine-Threonine Kinases
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TAO1 protein kinase
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MAP Kinase Kinase Kinases
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Paclitaxel
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Nocodazole