Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
Division of Oncogenomics, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
J Cell Sci. 2022 Oct 1;135(19). doi: 10.1242/jcs.259856. Epub 2022 Oct 6.
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.
细胞大小在细胞类型之间有所差异，但受到细胞内在和外在机制的严格调控。细胞大小的控制对细胞功能很重要，在癌症中经常观察到细胞大小的变化。在这里，我们揭示了 SETD2 在调节细胞大小方面的作用。SETD2 是一种赖氨酸甲基转移酶和肿瘤抑制蛋白，参与转录、RNA 加工和 DNA 修复。在分子水平上，SETD2 最著名的是通过其 Set2-Rbp1 相互作用（SRI）结构域与 RNA 聚合酶 II 相关联，并在转录过程中甲基化组蛋白 H3 上的赖氨酸 36（H3K36）。使用多种独立的扰动策略，我们确定 SETD2 是全球蛋白质合成率和细胞大小的负调节剂。我们提供的证据表明，H3K36 去甲基酶 KDM4A 或致癌组蛋白 H3.3K36M 的过表达也会增加细胞大小。此外，诱饵 SRI 结构域的异位过表达也会增加细胞大小，这表明 SETD2 通过其 SRI 结构域与相关底物结合。这些数据为 SETD2 在调节细胞生理方面的核心作用提供了依据，并需要进一步研究来区分 SETD2 在癌症发展中的不同功能。
