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J Biol Chem. 2018 Aug 17;293(33):12770-12780. doi: 10.1074/jbc.RA118.002890. Epub 2018 Jun 29.

Identification of Rpl29 as a major substrate of the lysine methyltransferase Set7/9.

Author information

From the Department of Epigenetics and Molecular Carcinogenesis, and.
the Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957.
the Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas 77030.
Cell Signaling Technology Inc., Danvers, Massachusetts 01923, and.
the Structural Genomics Consortium, and.
the Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
From the Department of Epigenetics and Molecular Carcinogenesis, and


Set7/9 (also known as Set7, Set9, Setd7, and Kmt7) is a lysine methyltransferase that catalyzes the methylation of multiple substrates, including histone H3 and non-histone proteins. Although not essential for normal development and physiology, Set7/9-mediated methylation events play important roles in regulating cellular pathways involved in various human diseases, making Set7/9 a promising therapeutic target. Multiple Set7/9 inhibitors have been developed, which exhibit varying degrees of potency and selectivity in vitro However, validation of these compounds in vivo has been hampered by the lack of a reliable cellular biomarker for Set7/9 activity. Here, we report the identification of Rpl29, a ribosomal protein abundantly expressed in all cell types, as a major substrate of Set7/9. We show that Rpl29 lysine 5 (Rpl29K5) is methylated exclusively by Set7/9 and can be demethylated by Lsd1 (also known as Kdm1a). Rpl29 is not a core component of the ribosome translational machinery and plays a regulatory role in translation efficiency. Our results indicate that Rpl29 methylation has no effect on global protein synthesis but affects Rpl29 subcellular localization. Using an Rpl29 methylation-specific antibody, we demonstrate that Rpl29K5 methylation is present ubiquitously and validate that (R)-PFI-2, a Set7/9 inhibitor, efficiently reduces Rpl29K5 methylation in cell lines. Thus, Rpl29 methylation can serve as a specific cellular biomarker for measuring Set7/9 activity.


Lsd1; Rpl29; Set7/9; biomarker; epigenetics; histone methylation; post-translational modification (PTM); ribosome function

[Available on 2019-08-17]
[Indexed for MEDLINE]

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