DNA Damage Triggers the Nuclear Accumulation of RASSF6 Tumor Suppressor Protein via CDK9 and BAF53 To Regulate p53 Target Gene Transcription

ABSTRACT

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. BAF53 silencing or BAF60a 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.

KEYWORDS:

• apoptosis
• BAF53
• BAF60a
• CDK9
• p53
• RASSF6
• signal transduction
• tumor suppressor

Declaration of Interests

The authors declare no conflict of interest.

SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

We thank Yuki Nakashima for technical support.

J.A.K., S.H., and Y.H. designed the experiments and wrote the manuscript. J.A.K. performed the experiments. T.S. supported the image analysis. C.K.S., H.I., J.M., K.A.-M., and H.N. critically read the manuscript and contributed to its preparation.

This work was funded by the Japan Society for the Promotion of Science (JSPS) (17K08624, 19H03414). J.A.K. and C.K.S. are supported by the MEXT scholarship.

We declare no competing interests.