Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the protein kinases ATM and ATR following chromosomal breakage prevents initiation of DNA replication and entry into mitosis. However, the effects of ATM and ATR activation in cells already progressing through mitosis are poorly understood. Here we report that ATM and ATR activation induced by DNA double-strand breaks (DSBs) inhibits centrosome-driven spindle assembly in Xenopus laevis mitotic egg extract and somatic cells, delaying mitotic progression. Using a cDNA expression library to screen for ATM and ATR substrates, we identified centrosomal protein CEP63 as an ATM and ATR target required for normal spindle assembly. ATM and ATR phosphorylate Xenopus CEP63 (XCEP63) on Ser 560 and promote its delocalization from the centrosome. Suppression of ATM and ATR activity or mutation of XCEP63 Ser 560 to Ala prevented spindle assembly defects. Consistently, inactivation of the CEP63 gene in avian DT40 cells impaired spindle assembly and prevented ATM- and ATR-dependent effects on mitosis. These data indicate that ATM and ATR control mitotic events in vertebrate cells by targeting CEP63 and centrosome dependent spindle assembly.
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PMID:An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63. 1918 92

The DNA damage checkpoint prevents the onset of DNA replication and mitosis when cells are exposed to genotoxic stress. However, it is not clear how cells react to DNA damage, in particular to DNA double strand breaks (DSBs) once they are in mitosis. Using Xenopus laevis egg extract as model system we have uncovered an ATM and ATR dependent checkpoint that targets centrosome dependent spindle assembly in the presence of chromosome breaks. This pathway relies on the phosphorylation by ATM and ATR of a novel centrosomal protein CEP63. We showed that CEP63 is required for proper spindle assembly in Xenopus and chicken DT40 cells. Phosphorylation of CEP63 by ATM and ATR leads to its delocalization from centrosomes and impairs its ability to promote centrosome dependent spindle assembly. These findings further support links uncovered in other model systems between the DNA damage checkpoint and centrosome in maintaining genome stability.
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PMID:An ATM and ATR dependent pathway targeting centrosome dependent spindle assembly. 1950 6