ATM is activated by mitotic stress and suppresses centrosome amplification in primary but not in tumor cells.
Centrosome amplification has been proposed to contribute to the development of aneuploidy and genome instability. Here, we show that Ataxia-Telangiectasia Mutated (ATM) is localized to the centrosome and co-purified with gamma-tubulin. The importance of ATM in centrosome duplication is demonstrated in Atm-deficient primary mouse embryonic fibroblasts that display centrosome amplification. Interestingly, centrosome amplification was not observed in tumor cell lines derived from Atm and p21 double deficient mouse. Our results also indicate that both p53 and p21 operate in the same pathway as ATM in regulating centrosome biogenesis. Finally, a potential role of ATM in spindle checkpoint regulation is demonstrated by which ATM protein is activated by mitotic stress. These results suggest a role of ATM in spindle checkpoint regulation and indicate that ATM suppresses genome instability and cellular transformation by regulating centrosome biogenesis.
Shen
Kate
K
Karmanos Cancer Institute, School of Medicine, Wayne State University, 110 E. Warren Ave., Detroit, MI 48201, USA.
Wang
Yaolin
Y
Brooks
S C
SC
Raz
Avraham
A
Wang
Y Alan
YA
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D042822:Genomic Instability; D051379:Mice; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases