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HUSH Complex: Opportunities for cancer immunotherapy

By Athavan Arulalagan

July 19, 2022

UPDATED 12:00 PM EST



[Photo Credit: Science.org]


Invasion of the mammalian genome by mobile genetic elements such as viral DNA (HIV) or transposons is a constant, pervasive threat which has shaped our genome. In some cases, the invasion has the positive impact of driving genome innovation through increased expression of specific genetic sequences with functions in pathogen defence. Yet, regulation of the chromosomes is vital to maintain genomic integrity. The major defence strategies to combat these issues include structural modification of chromatin to inaccessible heterochromatin in order to silence mobile elements. The Human Silencing Hub (HUSH) has been discovered as monitoring the repression of mobile transposons in humans as well as integrated lentiviruses in pluripotent stem cells and differentiated stem cells signifying its importance in protecting a large variety of somatic cell lines.

The HUSH complex uses effectors to enable chromatin compaction and anchors HUSH to the target locus for additional protection. Recent studies into the activity of the complex have revealed how the underlying mechanism to differentiate between self and non-self DNA through detection of intron sequences – providing versatile protection and its unique ability to repress sequences without previous exposure as part of its innate immune response. This is possible as mammalian genes within the genome comprise of coding exons within a vast sea of non-coding introns whilst cDNA, on the other hand, is formed from reverse transcription of intron-less RNA allowing for its recognition. The selective, evolutionary pressure for a compact genome in retroelements poses a major challenge in overcoming the protection provided by HUSH hence viruses often use methods such as degradation of the complex to evade its protection.

Inactivation of the HUSH complex has a multitude of impacts on cells and tissues which can be used in order to develop and improve upon existing medical strategies. Understanding the HUSH complex allows for better targeting and development of gene therapies for a wide array of conditions. Additionally, inactivation of HUSH has been seen to increase expression of transposons, specifically long interspersed element-1s (LINE-1s) which are responsible for the production of double stranded RNAs (dsRNA) – initiating an immune response within the cell. Reactivation of LINE-1s and other endogenous retroviruses is accompanied by an innate immune response resulting in increased production of interferons which act to inhibit viral replication within infected cells and increased inflammation representing the heightened immune response. This suggests that the HUSH complex may be directly linked as a causative factor in the pathogenesis of autoimmune disorders.

Conversely, HUSH is seen as a new target for cancer immunotherapies. Inactivation of the complex in tumours or surrounding tissues can be used to heighten the anti-tumour immune response and assist in preventing the growth and metastasis of the cancer. Activation of specific interferons however is associated with increased cancer progression and worsened disease outcome hence rigorous testing is required to reliably establish the feasibility of such treatments. To conclude, the discovery opens a large number of possibilities to future treatments and enhances our understanding of the immune response within the nucleus.


References:

"Q&A: The HUSH Complex – A Gatekeeper Of Type I Interferon Through Epigenetic Regulation Of LINE-1 Elements". Qmul.Ac.Uk, 2022, https://www.qmul.ac.uk/blizard/about/news/items/qa-the-hush-complex--a-gatekeeper-of-type-i-interferon-through-epigenetic-regulation-of-line-1-elements.html.

Seczynska, Marta et al. "Genome Surveillance By HUSH-Mediated Silencing Of Intronless Mobile Elements". Nature, vol 601, no. 7893, 2021, pp. 440-445. Springer Science And Business Media LLC, https://doi.org/10.1038/s41586-021-04228-1.

Tunbak, Hale et al. "The HUSH Complex Is A Gatekeeper Of Type I Interferon Through Epigenetic Regulation Of LINE-1S". Nature Communications, vol 11, no. 1, 2020. Springer Science And Business Media LLC, https://doi.org/10.1038/s41467-020-19170-5.

"Viral 'Fossils' In Our DNA May Help Us Fight Infection". Science.Org, 2022, https://www.science.org/content/article/viral-fossils-our-dna-may-help-us-fight-infection.



Figure 1 - [Credit - science.org]


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