Silencing by the HUSH Epigenetic Transcriptional Repressor Complex

Retroviral and retrotransposon invasion pose a constant threat to genome integrity and have driven the evolution of host defense pathways able to counter these attacks. The human silencing hub (HUSH complex) is an epigenetic transcriptional repressor complex that recognizes and silences newly integrated retroelements through the establishment of ectopic heterochromatin and chromatin compaction. HUSH provides a genome-wide immunosurveillance system whose challenging task is to detect and silence any newly integrated retroelements, and it thus plays a key role in host defense. To distinguish self from nonself genomic DNA, HUSH recognizes long single-exon (intronless) DNA, the essential hallmark of reverse transcription. Retroelements, being RNA derived, lack classical, noncoding cellular introns, so a long, intronless sequence of DNA is the abnormal molecular pattern that allows HUSH to distinguish invading retroelements from intron-containing host genes. As a newly identified component of the innate immune system, HUSH protects the genome from the reverse flow of genetic information from RNA to DNA, revealing an unanticipated mechanism of postintegration genome immunity.