The HUSH complex is a molecular machinery within human cells, composed of specific proteins that regulate cellular processes. It contributes to the stability and proper functioning of the cell’s genetic material, helping maintain order within our DNA.
Unveiling the Components
The HUSH complex consists of three primary protein subunits: M-phase phosphoprotein 8 (MPP8), Periphilin (PHPLN1), and Transcription Activation Suppressor (TASOR), also known as FAM208A. TASOR serves as a central scaffold, providing the framework for the other subunits to bind and assemble the complex.
MPP8 contains a chromodomain that interacts with trimethylated lysine 9 of histone H3 (H3K9me3), a modification linked to gene silencing. Periphilin binds to nascent, intronless RNA molecules. This combined recognition by Periphilin and MPP8 is essential for the HUSH complex to localize to its target sites.
Primary Functions
The HUSH complex primarily functions in gene silencing, a process that turns off specific genes. A major focus is regulating parasitic DNA elements like retrotransposons and endogenous retroviruses (ERVs). These “jumping genes” can move and replicate, potentially causing instability.
By silencing these mobile genetic elements, the HUSH complex contributes to maintaining genome stability, preventing unwanted genetic activity. It also plays a role in repressing newly integrated viral DNA, acting as a defense mechanism against foreign genetic material, safeguarding the cellular blueprint.
Regulation of Gene Expression
The HUSH complex regulates gene expression by establishing a repressive chromatin state through heterochromatin formation. The complex is recruited to specific genomic loci, often those rich in H3K9me3, a histone modification signaling transcriptional repression.
At the target site, HUSH recruits proteins like the histone methyltransferase SETDB1 and the ATPase MORC2. SETDB1 adds trimethyl groups to lysine 9 of histone H3 (H3K9me3) on nearby nucleosomes, spreading this repressive mark. This creates a compact, inaccessible chromatin structure, known as heterochromatin, which blocks gene transcription.
Periphilin’s binding to nascent intronless RNA transcripts is a key mechanism for HUSH to identify targets like retrotransposons. This RNA binding, combined with MPP8’s recognition of H3K9me3, anchors the complex at the genomic location. This targeted recruitment ensures the repressive machinery is precisely delivered to the elements that need to be silenced.
The HUSH complex also interacts with components of the nuclear exosome targeting (NEXT) complex, such as ZCCHC8. This interaction facilitates the decay of RNA transcripts from retrotransposons, further contributing to their silencing. These coordinated actions provide a robust defense against disruptive genetic elements.
Implications for Health
The proper functioning of the HUSH complex has widespread implications for human health, primarily due to its role in maintaining genome integrity. Dysregulation can lead to various cellular dysfunctions and contribute to disease. Its ability to silence retrotransposons is relevant in preventing genomic instability.
In cancer, a compromised HUSH complex can lead to uncontrolled retrotransposon activation, contributing to genomic rearrangements and tumor growth. MPP8, a HUSH component, is often downregulated in cancers, and its depletion can cause DNA damage. Targeting the HUSH complex could be a strategy for cancer immunotherapies by inducing an anti-tumor immune response.
The HUSH complex also defends against viral infections. It silences integrated retroviruses like HIV and can repress herpes simplex virus 1 (HSV-1) genomes. The HSV-1 viral protein ICP0 can degrade MORC2, a protein collaborating with HUSH, counteracting its repressive activity and allowing viral reactivation. Understanding these interactions opens avenues for developing new antiviral therapeutic strategies.