ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Jinli Wang; Nikole L Fendler; Ashutosh Shukla; Shwu-Yuan Wu; Ashwini Challa; Jeon Lee; Lukasz A Joachimiak; John D Minna; Cheng-Ming Chiang; Seychelle M Vos; Iván D'Orso

doi:10.1016/j.molcel.2024.10.020

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Mol Cell. 2024 Nov 8:S1097-2765(24)00860-8. doi: 10.1016/j.molcel.2024.10.020. Online ahead of print.

Authors

Affiliations

¹ Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
² Massachusetts Institute of Technology, Department of Biology, Cambridge, MA, USA.
³ Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Lydia Hill Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Massachusetts Institute of Technology, Department of Biology, Cambridge, MA, USA; Howard Hughes Medical Institute, Cambridge, MA, USA.
⁹ Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected].

PMID: 39532099
DOI: 10.1016/j.molcel.2024.10.020

Abstract

The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription. Second, ARF targets the RUNX family transcription factor 1 (RUNX1) to selectively tune gene transcription. Consistently, ARF loss triggers RUNX1- and PAF1c-dependent transcriptional activation of pro-growth ligands (growth differentiation factor/bone morphogenetic protein [GDF/BMP]), promoting a cell-intrinsic GDF/BMP-Smad1/5 axis that aberrantly induce cell growth. Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.

Keywords: ARF; CDKN2A; PAF1; RNA polymerase II; RUNX; cell proliferation; p53; transcription; tumor suppressor; tumorigenesis.