Oncotarget

Research Papers:

UV-induced proteolysis of RNA polymerase II is mediated by VCP/p97 segregase and timely orchestration by Cockayne syndrome B protein

Jinshan He, Qianzheng Zhu, Gulzar Wani and Altaf A. Wani _

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Oncotarget. 2017; 8:11004-11019. https://doi.org/10.18632/oncotarget.14205

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Abstract

Jinshan He1,*, Qianzheng Zhu1,*, Gulzar Wani1, Altaf A. Wani1,2,3

1Department of Radiology, The Ohio State University, Columbus, OH 43210, USA

2Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA

3James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

*These authors contributed equally to this work

Correspondence to:

Qianzheng Zhu, email: [email protected]

Altaf Wani, email: [email protected]

Keywords: RNA polymerase II, valosin-containing protein, ubiquitin, cockayne syndrome B, von hippel-lindau tumor suppressor protein

Received: October 24, 2016     Accepted: December 20, 2016     Published: December 26, 2016

ABSTRACT

RNA polymerase II (RNAPII) acts as a damage sensor for transcription-coupled nucleotide excision repair (TC-NER) and undergoes proteolytic clearance from damaged chromatin by the ubiquitin-proteasome system (UPS). Here, we report that Valosin-containing protein (VCP)/p97, a druggable oncotarget, is essential for RNAPII’s proteolytic clearance in mammalian cells. We show that inhibition of VCP/p97, or siRNA-mediated ablation of VCP/p97 and its cofactors UFD1 and UBXD7 severely impairs ultraviolet radiation (UVR)-induced RNAPII degradation. VCP/p97 interacts with RNAPII, and the interaction is enhanced by Cockayne syndrome B protein (CSB). However, the VCP/p97-mediated RNAPII proteolysis occurs independent of CSB. Surprisingly, CSB enhances UVR-induced RNAPII ubiquitination but delays its turnover. Additionally, VCP/p97-mediated RNAPII turnover occurs with and without Von Hippel-Lindau tumor suppressor protein (pVHL), a known substrate receptor of Elongin E3 ubiquitin ligase for RNAPII. Moreover, pVHL re-expression improves cell viability following UVR. Whereas, VCP/p97 inhibition decreases cell viability and enhances a low-dose UVR killing in presence of pVHL. These findings reveal a function of VCP/p97 segregase in UVR-induced RNAPII degradation in mammalian cells, and suggest a role of CSB in coordinating VCP/p97-mediated extraction of ubiquitinated RNAPII and CSB itself from chromatin.


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