SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

Hapke, Robert; Venton, Lindsay; Rose, Kristie L.; Sheng, Quanhu; Reddy, Anupama; Jones, Angela L.; Rathmell, W. Kimryn

doi:10.1101/2020.10.26.354902

Cited by 2 publications

(3 citation statements)

References 46 publications

(3 reference statements)

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“…In confirmation of our findings, a recent preprint study also found a negative role for SETD2 in translation regulation in clear cell renal cell carcinoma (ccRCC; Hapke et al 2020). SETD2 inactivating mutations are frequently found in multiple types of cancer, including ccRCC (Dalgliesh et al 2010; Duns et al 2010; Gerlinger et al 2012; Sato et al 2013; Bihr et al 2019), high-grade gliomas (Fontebasso et al 2013), and leukemias (Zhang et al 2012; Zhu et al 2014; Mar et al 2014).…”

Section: Discussionsupporting

confidence: 91%

“…Although ribosomal proteins are common contaminants in co-IP experiments (Pardo and Choudhary 2012), it might be interesting to determine if SETD2 interacts with specific component of the ribosome via the SRI domain, and whether this interaction is relevant for the regulation of protein synthesis by SETD2. In confirmation of our findings, a recent preprint study also found a negative role for SETD2 in translation regulation in clear cell renal cell carcinoma (ccRCC; Hapke et al 2020). SETD2 inactivating mutations are frequently found in multiple types of cancer, including ccRCC (Dalgliesh et al 2010;Duns et al 2010;Gerlinger et al 2012;Sato et al 2013;Bihr et al 2019), high-grade gliomas (Fontebasso et al 2013), and leukemias (Zhang et al 2012;Zhu et al 2014;Mar et al 2014).…”

Section: Discussionsupporting

confidence: 88%

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SETD2 negatively regulates cell size through its catalytic activity and SRI domain

Molenaar

Kwesi-Maliepaard

Silva

et al. 2021

Preprint

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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 cells. Here we uncover a non-canonical role of SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription regulation, 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. Although most of SETD2’s cellular functions have been linked to this activity, several non-histone substrates of SETD2 have recently been identified – some of which have been linked to novel functions of SETD2 beyond chromatin regulation. Using multiple, independent perturbation strategies we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that this function is dependent on the catalytic activity of SETD2 but independent of H3K36 methylation. Paradoxically, ectopic overexpression of a decoy SRI domain also 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.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

SETD2 negatively regulates cell size through its catalytic activity and SRI domain

Molenaar

Kwesi-Maliepaard

Silva

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In support of our findings, a recent preprint study also found a negative role for SETD2 in protein synthesis regulation in clear cell renal cell carcinoma (ccRCC) (Hapke et al 2020). SETD2 inactivating mutations are frequently found in multiple types of cancer, including ccRCC (Dalgliesh et al 2010;Duns et al 2010;Gerlinger et al 2012;Sato et al 2013;Bihr et al 2019), high-grade gliomas (Fontebasso et al 2013), and leukemias (Zhang et al 2012;Zhu et al 2014;Mar et al 2014).…”

Section: Discussionsupporting

confidence: 88%

The histone methyltransferase SETD2 negatively regulates cell size

Molenaar

Malik

Silva

et al. 2022

Journal of Cell Science

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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.

show abstract

SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

Cited by 2 publications

References 46 publications

SETD2 negatively regulates cell size through its catalytic activity and SRI domain

SETD2 negatively regulates cell size through its catalytic activity and SRI domain

The histone methyltransferase SETD2 negatively regulates cell size

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