MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation.

Apoorva Baluapuri,Ashwin Narain,Julia Hofstetter,Armin Wiegering,Peter Gallant,Susanne Walz,Robert Düster,Patrick Cramer,Bikash Adhikari,Matthias Geyer,Pranjali Bhandare,Martin Eilers,Lisa Anna Jung,Jessica Denise Schwarz,Markus Vogt,Elmar Wolf,Theresa Endres,Hans Michael Maric,Nevenka Dudvarski Stanković ,Seychelle M Vos ,Jens T Vanselow ,Shuangyan Wang ,Andreas Schlösser

doi:10.1016/j.molcel.2019.02.031

Apoorva Baluapuri, Ashwin Narain + Show 21 more

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https://doi.org/10.1016/j.molcel.2019.02.031

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SummaryThe MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.

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Deregulated and enhanced expression of the MYC proto-oncogene contributes to the development of most human tumors (Dang, 2012; Schaub et al, 2018), and mouse models demonstrate that many cancer cells depend on high levels of MYC (Gabay et al, 2014)
Using mass spectrometry of both MYC and polymerase II (Pol II) complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF
These results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth

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Introduction

Deregulated and enhanced expression of the MYC proto-oncogene contributes to the development of most human tumors (Dang, 2012; Schaub et al, 2018), and mouse models demonstrate that many cancer cells depend on high levels of MYC (Gabay et al, 2014). A large body of evidence demonstrates that MYC is a nuclear protein that forms a complex with the MYC-associated factor X (MAX) and binds to E-box-containing DNA (CACGTG) (Carroll et al, 2018). Productive elongation requires the assembly of a highly processive and fast transcriptional apparatus (Jonkers and Lis, 2015). This assembly process entails a series of defined structural transitions of Pol II that are mediated by the differential association of Pol II with auxiliary and regulatory proteins. Recent evidence indicates that SPT5 travels with Pol II, enhances its processivity (Fitz et al, 2018), and is required for transcriptional elongation (Henriques et al, 2018; Shetty et al, 2017). SPT5 enhances processivity by binding to the DNA exit region on Pol II, facilitating re-winding of upstream DNA and preventing aberrant backtracking of Pol II (Bernecky et al, 2017; Ehara et al, 2017)

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