Prion protein transcription is auto-regulated through dynamic interactions with G-quadruplex motifs in its own promoter

Publication date: Available online 10 January 2020Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory MechanismsAuthor(s): Prashant Pradhan, Ankit Srivastava, Jasdeep Singh, Banhi Biswas, Akanksha Saini, Ibrar Siddique, Pooja Kumari, Md. Asim Khan, Akhilesh Mishra, Pramod Kumar Yadav, Shivani Kumar, Neel Sarovar Bhavesh, Prasanna Venkatraman, Perumal Vivekanandan, Bishwajit KunduAbstractCellular prion protein (PrP) misfolds into an aberrant and infectious scrapie form (PrPSc) that lead to fatal transmissible spongiform encephalopathies (TSEs). Association of prions with G-quadruplex (GQ) forming nucleic acid motifs has been reported, but implications of these interactions remain elusive. Herein, we show that the promoter region of the human prion gene (PRNP) contains two putative GQ motifs (Q1 and Q2) that assume stable, hybrid, intra-molecular quadruplex structures and bind with high affinity to PrP. Here, we investigate the ability of PrP to bind to the quadruplexes in its own promoter. We used a battery of techniques including SPR, NMR, CD, MD simulations and cell culture-based reporter assays. Our results show that PrP auto-regulates its expression by binding and resolving the GQs present in its own promoter. Furthermore, we map this resolvase-like activity to the N-terminal region (residues 23–89) of PrP. Our findings highlight a positive transcriptional-translational feedback regulation of the PRNP gene by PrP through dynamic unwinding of GQs in its promoter...

Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms - January 11, 2020 Category: Genetics & Stem Cells Source Type: research