Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation
Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation
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DOI：
10.1038/sj.emboj.7601212
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发表时间：
2006-07-26
期刊：
影响因子：
11.4
通讯作者：
Nishina, Hiroshi
中科院分区：
文献类型：
--
作者：
Kitagawa, Daiju;Kajiho, Hiroaki;Nishina, Hiroshi
应激激活蛋白激酶/c-Jun N端激酶（SAPK/JNK）对多种应激刺激作出反应，控制细胞周期进入、细胞凋亡和衰老等细胞命运。紫外线照射和化学试剂等损伤基因组 DNA 的刺激会诱导 SAPK/JNK 信号通路的激活。然而，尚不清楚由于 DNA 损伤而在细胞核中产生的信号如何传递到细胞质中的 SAPK/JNK。在这里，我们报道了 HeLa 细胞中核成分 Daxx 和 Ras 关联结构域家族 1C (RASSF1C) 将 DNA 损伤与 SAPK/JNK 激活联系起来。为了应对 DNA 损伤，位于早幼粒细胞白血病核体 (PML-NB) 中的 Daxx 发生泛素化和降解。 RASSF1C 是一种肿瘤抑制因子，也是新发现的 Daxx 结合伴侣，在 PML-NB 中由 Daxx 组成型锚定，但当 Daxx 降解时从细胞核中释放。释放的 RASSF1C 易位至细胞质微管并参与 SAPK/JNK 的激活。我们的数据定义了一种新机制，PML-NB 中的 Daxx - RASSF1C 复合物将核 DNA 损伤与细胞质 SAPK/JNK 信号通路耦合。
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.