PTEN interacts with RNA polymerase II to dephosphorylate polymerase II C-terminal domain
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Ata Abbas1,5, Todd Romigh1 and Charis Eng1,2,3,4
1 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195 OH, USA
2 Taussig Cancer Institute, Cleveland Clinic, Cleveland, 44195 OH, USA
3 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, 44116 OH, USA
4 Germline High Risk Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, 44116 OH, USA
5 Present address: Division of Hematology Oncology, Department of Medicine, Case Western Reserve University, Cleveland, 44106 OH, USA
|Charis Eng,||email:||[email protected]|
Keywords: phosphatase and tensin homolog (PTEN); cowden syndrome; PTEN hamartoma tumor syndrome; RNA polymerase II; Pol II CTD dephosphorylation
Received: June 21, 2019 Accepted: July 17, 2019 Published: August 13, 2019
Gene transcription is a highly complex and strictly regulated process. RNA polymerase II (Pol II) C-terminal domain (CTD) undergoes massive cycles of phosphorylation and dephosphorylation during the process of gene transcription. These post-translational modifications of CTD provide an interactive platform for various factors required for transcription initiation, elongation, termination, and co-transcriptional RNA processing. Pol II CTD kinases and phosphatases are key regulators and any deviation may cause genome-wide transcriptional dysregulation leading to various pathological conditions including cancer. PTEN, a well known tumor suppressor, is one of the most commonly somatically altered in diverse malignancies. When mutated in the germline, PTEN causes cancer predisposition. Numerous studies have demonstrated that PTEN regulates the expression of hundreds of genes, however, no mechanism is known so far. PTEN is a dual specificity phosphatase, using both lipid and protein as substrates. In the present study, we demonstrate that PTEN interacts with the RNA Pol II and that PTEN expression is inversely correlated with global phosphorylation of Pol II CTD. Furthermore, PTEN dephosphorylates Pol II CTD in vitro with a significant specificity for Ser5p. Interestingly, ChIP-seq data analysis revealed that PTEN globally binds to promoter proximal regions, and PTEN loss increases genome-wide Pol II Ser5p occupancy, suggest that PTEN is a Pol II CTD phosphatase. Our observations demonstrate an unexplored function of PTEN with the potential of global transcriptional regulation, adding a new dimension to somatic carcinogenesis and germline cancer predisposition.
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