Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental Universitygrid.265073.5, Tokyo, Japan.
Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.
Mol Cell Biol. 2022 Feb 17;42(2):e0031021. doi: 10.1128/MCB.00310-21. Epub 2021 Dec 13.
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. silencing or silencing 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.
RASSF6 是肿瘤抑制 Ras 相关结构域家族（RASSF）蛋白的成员，通过 p53 调节细胞周期停滞和细胞凋亡，发挥肿瘤抑制作用。我们之前报道过，RASSF6 可阻断 MDM2 介导的 p53 降解并增强 p53 的表达。在本研究中，我们证实 RASSF6 具有核定位和核输出信号，并且 DNA 损伤可触发 RASSF6 的核积累。我们发现 RASSF6 可直接与 SWI/SNF 复合物的组成部分 BAF53 结合。DNA 损伤诱导 CDK9 介导的 BAF53 磷酸化，增强了与 RASSF6 的相互作用，增加了核内 RASSF6 的含量。随后，RASSF6 增强了 BAF53 与 SWI/SNF 复合物的另一个组成部分 BAF60a 之间的相互作用，并进一步促进了 BAF53 与 BAF60a 与 p53 的相互作用。沉默或 沉默可减弱 RASSF6 介导的 p53 靶基因转录和细胞凋亡。因此，RASSF6 参与了 DNA 损伤诱导的复合物形成的调节，包括 BAF53、BAF60a 和 p53。
