DNA Damage Triggers the Nuclear Accumulation of RASSF6 Tumor Suppressor Protein via CDK9 and BAF53 To Regulate p53 Target Gene Transcription
DNA Damage Triggers the Nuclear Accumulation of RASSF6 Tumor Suppressor Protein via CDK9 and BAF53 To Regulate p53 Target Gene Transcription
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DOI：
10.1128/mcb.00310-21
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发表时间：
2022-02-01
影响因子：
5.3
通讯作者：
Hata，Yutaka
中科院分区：
文献类型：
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作者：
Kuleape，Joshua Agbemefa;Hossain，Shakhawoat;Hata，Yutaka
RASSF 6是肿瘤抑制因子Ras相关结构域家族（RASSF）蛋白的成员，通过p53调控细胞周期阻滞和凋亡，并发挥肿瘤抑制作用。我们先前报道RASSF 6阻断MDM 2介导的p53降解并增强p53表达。在这项研究中，我们证明了RASSF 6具有核定位和核输出信号，并且DNA损伤触发了RASSF 6的核积累。我们发现RASSF 6直接与SWI/SNF复合物的组分BAF 53结合。DNA损伤诱导CDK 9介导的BAF 53磷酸化，这增强了与RASSF 6的相互作用并增加了细胞核中RASSF 6的量。随后，RASSF 6增强了BAF 53和BAF 60 a（SWI/SNF复合物的另一个组分）之间的相互作用，并进一步促进了BAF 53和BAF 60 a与p53的相互作用。BAF 53沉默或BAF 60 a沉默减弱了RASSF 6介导的p53靶基因转录和凋亡。因此，RASSF 6参与调节DNA损伤诱导的复合物形成，包括BAF 53、BAF 60 a和p53。
RASSF6, a member of the tumor suppressor Ras-association domain family (RASSF) proteins, regulates cell cycle arrest and apoptosis via p53 and plays a tumor suppressor role. We previously reported that RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. In this study, we demonstrated that RASSF6 has nuclear localization and nuclear export signals and that DNA damage triggers the nuclear accumulation of RASSF6. We found that RASSF6 directly binds to BAF53, the component of SWI/SNF complex. DNA damage induces CDK9-mediated phosphorylation of BAF53, which enhances the interaction with RASSF6 and increases the amount of RASSF6 in the nucleus. Subsequently, RASSF6 augments the interaction between BAF53 and BAF60a, another component of the SWI/SNF complex, and further promotes the interaction of BAF53 and BAF60a with p53.BAF53silencing orBAF60asilencing attenuates RASSF6-mediated p53 target gene transcription and apoptosis. Thus, RASSF6 is involved in the regulation of DNA damage-induced complex formation, including BAF53, BAF60a, and p53.