Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379.
The Chk2 protein kinase protects genome integrity by promoting cell cycle arrest or apoptosis in response to DNA double-strand breaks, and Chk2 mutations are found in both familial and sporadic cancers. Exposure of cells to ionizing radiation (IR) or radiomimetic drugs induces Chk2 phosphorylation by ATM, followed by Chk2 oligomerization, auto-/transphosphorylation, and activation. Here we demonstrate that Chk2 is ubiquitinated upon activation and that this requires Chk2 kinase activity. Serine 379 (S379) was identified as a novel IR-inducible autophosphorylation site required for ubiquitination of Chk2 by a Cullin 1-containing E3 ligase complex. Importantly, S379 was required for Chk2 to induce apoptosis in cells with DNA double-strand breaks. Thus, auto-/transphosphorylation of S379 is required for Chk2 ubiquitination and effector function.
Lovly
Christine M
CM
Department of Cell Biology and Physiology, Washington University School of Medicine, Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Yan
Ling
L
Ryan
Christine E
CE
Takada
Saeko
S
Piwnica-Worms
Helen
H
D002460:Cell Line; D064447:Checkpoint Kinase 2; D044842:Cullin Proteins / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011839:Radiation, Ionizing; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
C100318:Cullin 1; D044842:Cullin Proteins; D012694:Serine; D044767:Ubiquitin-Protein Ligases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases