The histone methyltransferase SETD2 negatively regulates cell size

Author:

Molenaar Thom M.1ORCID,Malik Muddassir1ORCID,Silva Joana2ORCID,Liu Ning Qing3ORCID,Haarhuis Judith H. I.4,Ambrosi Christina56ORCID,Kwesi-Maliepaard Eliza Mari1ORCID,van Welsem Tibor1,Baubec Tuncay578ORCID,Faller William J.2ORCID,van Leeuwen Fred19ORCID

Affiliation:

1. Netherlands Cancer Institute 1 Division of Gene Regulation , , 1066CX Amsterdam , The Netherlands

2. Netherlands Cancer Institute 2 Division of Oncogenomics , , 1066CX Amsterdam , The Netherlands

3. Oncode Institute, Netherlands Cancer Institute 3 Division of Gene Regulation , , 1066CX Amsterdam , The Netherlands

4. Netherlands Cancer Institute 4 Division of Cell Biology , , 1066CX Amsterdam , The Netherlands

5. University of Zurich 5 Department of Molecular Mechanisms of Disease , , 8057 Zurich , Switzerland

6. Life Science Zurich Graduate School, University of Zurich and ETH Zurich 6 , CH-8057 Zurich , Switzerland

7. Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity 7 , Department of Biology , , 3584 CH Utrecht , The Netherlands

8. Utrecht University 7 , Department of Biology , , 3584 CH Utrecht , The Netherlands

9. Amsterdam UMC, University of Amsterdam 8 Department of Medical Biology , , 1105AZ Amsterdam , The Netherlands

Abstract

ABSTRACT Cell size varies between cell types but is tightly regulated by cell intrinsic and extrinsic mechanisms. Cell size control is important for cell function, and changes in cell size are frequently observed in cancer. Here, we uncover a role for SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription, RNA processing and DNA repair. At the molecular level, SETD2 is best known for associating with RNA polymerase II through its Set2-Rbp1 interacting (SRI) domain and methylating histone H3 on lysine 36 (H3K36) during transcription. Using multiple independent perturbation strategies, we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that overexpression of the H3K36 demethylase KDM4A or the oncohistone H3.3K36M also increase cell size. In addition, ectopic overexpression of a decoy SRI domain increased cell size, suggesting that the relevant substrate is engaged by SETD2 via its SRI domain. These data add a central role of SETD2 in regulating cellular physiology and warrant further studies on separating the different functions of SETD2 in cancer development.

Funder

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

KWF Kankerbestrijding

ZonMW

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Antoni van Leeuwenhoek Nederlands Kanker Instituut

Publisher

The Company of Biologists

Subject

Cell Biology

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