A novel Chk1/2-Lats2-14-3-3 signaling pathway regulates P-body formation in response to UV damage.
Proper response to DNA damage is essential for maintaining the integrity of the genome. Here we show that in response to ultraviolet (UV) radiation, the Lats2 tumor suppressor protein is phosphorylated predominantly by Chk1 and weakly by Chk2 at S408 in vivo, and that this process occurs at all stages of the cell cycle and leads to phosphorylation of 14-3-3γ on S59 by Lats2. Interaction of Lats2 and 14-3-3γ in vivo was confirmed by immunoprecipitation and western blot analysis. Phosphorylated 14-3-3γ translocates to the P-body, where mRNA degradation, translational repression and mRNA surveillance take place. Depletion of Lats2 or 14-3-3γ by siRNA inhibits P-body formation in response to UV, newly implicating Lats2 and 14-3-3 as regulators of P-body formation. By contrast, siRNA-mediated depletion of Lats1, a mammalian paralog of Lats2, showed no such effect. On the basis of these findings, we propose that the Chk1/2-Lats2-14-3-3 axis identified here plays an important role in connecting DNA damage signals to P-body assembly.
Department of Molecular Genetics, Research Institute for MicroFbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
Nobuhiro
N
Okada
Norikazu
N
Yabuta
Hirokazu
H
Suzuki
Yael
Y
Aylon
Moshe
M
Oren
Hiroshi
H
Nojima
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000528:radiation effects; D006801:Humans; D015388:Organelles / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation / Q000528:radiation effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011827:Radiation; D015398:Signal Transduction / Q000528:radiation effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
D048948:14-3-3 Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C406449:LATS2 protein, human; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases