Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation.
Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) responds to a variety of stress stimuli and controls cell fates such as cell cycle entrance, apoptosis and senescence. Stimuli such as ultraviolet irradiation and chemical reagents that damage genomic DNA induce the activation of the SAPK/JNK signaling pathway. However, it is unclear how the signal arising in the nucleus owing to DNA damage is transmitted to SAPK/JNK in the cytoplasm. Here, we report that the nuclear components Daxx and Ras-association domain family 1C (RASSF1C) link DNA damage to SAPK/JNK activation in HeLa cells. In response to DNA damage, Daxx localized in promyelocytic leukaemia-nuclear bodies (PML-NBs) undergoes ubiquitination and degradation. RASSF1C, a tumor suppressor and newly identified binding partner of Daxx, is constitutively anchored by Daxx in PML-NBs but is released from the nucleus when Daxx is degraded. This released RASSF1C translocates to cytoplasmic microtubules and participates in the activation of SAPK/JNK. Our data define a novel mechanism by which the Daxx-RASSF1C complex in PML-NBs couples nuclear DNA damage to the cytoplasmic SAPK/JNK signaling pathway.
Kitagawa
Daiju
D
The Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Kajiho
Hiroaki
H
Negishi
Takahiro
T
Ura
Seiji
S
Watanabe
Tomomi
T
Wada
Teiji
T
Ichijo
Hidenori
H
Katada
Toshiaki
T
Nishina
Hiroshi
H
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000201:enzymology*; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D020033:Protein Isoforms; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex