An Essential Signaling Function of Cytoplasmic NELFB is Independent of RNA Polymerase II Pausing

Authors

Haihui Pan, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA. Electronic address: haihui.pan@outlook.com.
Xiaolong Cheng, Department of Genomics & Precision Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010, USA.
Pedro Felipe Rodríguez, Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA.
Xiaowen Zhang, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA.
Inhee Chung, Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA.
Victor X. Jin, Institute of Health Equity and Cancer Center, The Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Wei Li, Department of Genomics & Precision Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010, USA.
Yanfen Hu, Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA.
Rong Li, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037, USA. Electronic address: rli69@gwu.edu.

Document Type

Journal Article

Publication Date

9-15-2023

Journal

The Journal of biological chemistry

DOI

10.1016/j.jbc.2023.105259

Abstract

The four-subunit negative elongation factor (NELF) complex mediates RNA polymerase II (Pol II) pausing at promoter-proximal regions. Ablation of individual NELF subunits destabilizes the NELF complex and causes cell lethality, leading to the prevailing concept that NELF-mediated Pol II pausing is essential for cell proliferation. Using separation-of-function mutations, we show here that NELFB function in cell proliferation can be uncoupled from that in Pol II pausing. NELFB mutants sequestered in the cytoplasm and deprived of NELF nuclear function still support cell proliferation and part of the NELFB-dependent transcriptome. Mechanistically, cytoplasmic NELFB physically and functionally interacts with pro-survival signaling kinases, most notably PI3K/AKT. Ectopic expression of membrane-tethered PI3K/AKT partially bypasses the role of NELFB in cell proliferation, but not Pol II occupancy. Together, these data expand the current understanding of the physiological impact of Pol II pausing and underscore the multiplicity of the biological functions of individual NELF subunits.

APA Citation

Pan, Haihui; Cheng, Xiaolong; Rodríguez, Pedro Felipe; Zhang, Xiaowen; Chung, Inhee; Jin, Victor X.; Li, Wei; Hu, Yanfen; and Li, Rong, "An Essential Signaling Function of Cytoplasmic NELFB is Independent of RNA Polymerase II Pausing" (2023). GW Authored Works. Paper 3391.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3391

Department

Biochemistry and Molecular Medicine