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TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control

DOI: 10.1038/s41467-020-18761-6 DOI Help

Authors: Christopher Douse (University of Cambridge) , Iva A. Tchasovnikarova (University of Cambridge School of Clinical Medicine) , Richard T. Timms (University of Cambridge School of Clinical Medicine) , Anna V. Protasio (University of Cambridge; University of Cambridge School of Clinical Medicine) , Marta Seczynska (University of Cambridge School of Clinical Medicine) , Daniil M. Prigozhin (University of Cambridge) , Anna Albecka (University of Cambridge; University of Cambridge School of Clinical Medicine) , James Wagstaff (MRC Laboratory of Molecular Biology) , James C. Williamson (University of Cambridge School of Clinical Medicine) , Stefan M. V. Freund (MRC Laboratory of Molecular Biology) , Paul J. Lehner (University of Cambridge School of Clinical Medicine) , Yorgo Modis (University of Cambridge; University of Cambridge School of Clinical Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 11235

Open Access Open Access

Abstract: The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits — TASOR, MPP8 and Periphilin — contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced transcriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA processing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. Structure-function analyses reveal TASOR bears a catalytically-inactive PARP domain necessary for targeted H3K9me3 deposition. We conclude that TASOR is a multifunctional pseudo-PARP that directs HUSH assembly and epigenetic regulation of repetitive genomic targets.

Journal Keywords: Chromatin immunoprecipitation; Gene silencing; Histone post-translational modifications; Transcriptional regulatory elements; X-ray crystallography

Diamond Keywords: Epigenetics

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 20/10/2020 10:34

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s41467-020-18761-6.pdf

Discipline Tags:

Biochemistry Genetics Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)