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Periphilin self-association underpins epigenetic silencing by the HUSH complex

DOI: 10.1093/nar/gkaa785 DOI Help

Authors: Daniil M. Prigozhin (University of Cambridge) , Christopher H. Douse (University of Cambridge) , Laura E Farleigh (University of Cambridge) , Anna Albecka (University of Cambridge) , Iva a. Tchasovnikarova (University of Cambridge) , Richard T Timms (University of Cambridge) , Shun-ichiro Oda (University of Cambridge) , Frank Adolf (University of Cambridge) , Stefan M. V. Freund (MRC Laboratory of Molecular Biology) , Sarah Maslen (MRC Laboratory of Molecular Biology) , Paul J Lehner (University of Cambridge) , Yorgo Modis (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 48 , PAGES 10313 - 10328

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 15916

Open Access Open Access

Abstract: Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR minimal core complex shows Periphilin forms an α-helical homodimer, bound by a single TASOR molecule. The NTD forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation at target loci.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

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