TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression.
Aurora-A, a conserved serine-threonine kinase, plays essential roles in mitosis. Aberrant upregulation of Aurora-A perturbs proper mitotic progression and results in a generation of multinucleated cells with centrosome amplification. The molecular mechanisms for these mitotic defects remain elusive. Here, we show that the overexpressed Aurora-A-induced mitotic defects depend on the telomeric protein TRF1. Live and fixed cell analyses revealed that Aurora-A overexpression in HeLa cells compromises chromosome biorientation, which leads to cytokinetic failure and tetraploidization with increased centrosome numbers. TRF1 depletion by small interfering RNAs or by tankyrase-1 overexpression suppresses Aurora-A-induced occurrence of unaligned chromosomes in metaphase, thus preventing the subsequent abnormalities. We found that Aurora-A binds and phosphorylates TRF1. When TRF1 knockdown cells are complemented with wild-type TRF1, Aurora-A-induced mitotic defects recur. By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A-induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability.
Division of Molecular Biotherapy, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Tomokazu
T
Ohishi
Toru
T
Hirota
Takashi
T
Tsuruo
Hiroyuki
H
Seimiya
D064127:Aurora Kinases; D018385:Centrosome / Q000502:physiology; D002877:Chromosomes, Human; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D038501:Tankyrases / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D038501:Tankyrases; D035321:Telomeric Repeat Binding Protein 1; C418109:TNKS protein, human