The crystal structure of MORC2, an effector of epigenetic silencing by the human silencing hub (HUSH). MORC2 forms ATP-dependent dimers and neuropathic mutations map to the ATP binding site, altering the dimerization dynamics of the molecule.
Many viruses, such as HIV and other retroviruses, splice or integrate their genome into the genome of a human cell as part of the infectious cycle. These stretches of integrated viral DNA can serve as templates for the production new virus particles, promoting the spread of infection. The human body has evolved a critical set of immune responses to prevent the production new virus particles from integrated viral DNA. In one these antiviral immune responses, the specific proteins within the cell modify the structure and chemical composition of the integrated viral DNA in a way that shuts down the expression of the genes and makes them inactive. Recent studies by Paul Lehner (CIMR/Dept. of Medicine) and Yorgo Modis (Molecular Immunity Unit, Dept. of Medicine) have shown that a human protein called MORC2 plays an essential role in shutting down integrated viral genes. However, the mechanism of this process remained unclear. The importance of MORC2 is highlighted by the fact that patients with certain mutations in the gene encoding MORC2 develop severe neuropathies including Charcot Marie Tooth disease and spinal muscular atrophy. In a new study published in Nature Communications, the Modis group used biochemical and biophysical approaches to gain a better understanding of how MORC2 contributes to viral gene silencing. The molecular structure of MORC2 was determined at near-atomic resolution, which, along with biochemical studies, revealed that MORC2 can attach to DNA and has a similar overall structure as a family of DNA repair enzymes. Moreover, MORC2 self-assembles in a highly regulated manner. Disease-causing mutations were found to perturb the self-assembly of MORC2. The self-assembly of DNA-bound MORC2 causes the DNA to become more compacted, which directly contributes to the repression of any viral genes within the DNA.
Integrated viral genomic DNA can remain dormant, or latent, in infected patients for many years without producing any virus, only to reemerge when the patient’s immune system is weakened or compromised, for example by a secondary infection or simply by old age. Latent viral genes are difficult to detect and there are currently no methods or treatments to eliminate them. Developing strategies to reactivate latent viral genes will facilitate diagnosis and clearance of viral infections including HIV while the patients are otherwise still healthy. One such strategy may be to develop a therapeutic to target the function of MORC2, and hence interfere with the repression of integrated viral genes. The new study by the Modis group will hopefully guide and inform future efforts to design such therapeutics.