How we HUSH jumping genes and viruses

Authors: Christopher H. Douse (Lund University)
Co-authored by industrial partner: No

Type: Diamond Annual Review Highlight

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 11235

Abstract: The human silencing hub (HUSH) is a complex of three proteins discovered in 2015. It plays a role in repressing the replication of retroviruses such as HIV and 'jumping genes' (transposons) that can move within the genome. HUSH works by regulating chromatin, the material that packages our genomes, in particular ways. However, until recently little was known about the molecular and structural mechanisms underpinning HUSH function. TASOR is the key scaffold protein of the HUSH complex. An international team of researchers investigated how TASOR features in HUSH assembly and regulates chromatin structure over transposons. They found that one end of the TASOR molecule contains a domain that is not needed for assembly but is critical for HUSH function. They used Diamond Light Source’s Macromolecular Crystallography (MX) beamlines I02 and I03 to screen datasets of native and SeMet crystals of this domain. Their resulting structure revealed that this part of TASOR resembles a domain from enzymes called PARPs that maintain genome stability. Close examination of the structure revealed that TASOR’s PARP domain is catalytically inactive – in other words, TASOR is a 'pseudo-PARP'. Although we now have anti-retroviral treatments for HIV that are very efficient at inhibiting actively replicating viruses, we are left with the challenge of clearing latent (dormant) viruses. Inhibiting or degrading HUSH might reactivate latent viruses, allowing existing treatments to clear the infection – a ‘shock and kill’ strategy. Knowing the structure of functionally critical domains of HUSH, like the TASOR pseudo-PARP domain, will help develop HUSH inhibitors.

Journal Keywords: Chromatin; Transposons; Epigenetics; Genome stability; Viral restriction

Diamond Keywords: Epigenetics

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 12/11/2021 14:52

Discipline Tags:

Life Sciences & Biotech Genetics Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)