Prof Paul Lehner; University of Cambridge
Paul Lehner trained in medicine and infectious diseases in London. He is the Sheila Joan Smith Professor of Immunology at the University of Cambridge and an Honorary Consultant in Infectious Diseases at Addenbrookes hospital. He uses functional genetic and proteomic technologies to study viral interactions with the human immune system. Prominent among his discoveries is his identification of the Human Silencing Hub (HUSH), an epigenetic transcriptional repressor complex which recognizes and silences DNA that has invaded the vertebrate genome.
Retrotransposition, the conversion of RNA to cDNA and subsequent genome integration is the predominant route by which our genome acquires new genetic material, with retro elements making up >40% of our genome. This acquisition of new genetic material may be beneficial, increasing genome diversity, or potentially catastrophic. Retrotransposition must therefore be tolerated but highly regulated. We discovered the ‘HUSH’ (Human Silencing Hub) complex, an epigenetic transcriptional repressor complex which silences invading DNA and defends the genome following retroelement attack. Our key question was ‘what are the unique features that allow HUSH to discriminate ‘self’ from ‘non-self’ genomic DNA? The unexpected answer was ‘introns’. Retroelements being RNA-derived, lack non-coding introns, and intronless cDNA, the hallmark of reverse transcription, therefore provides the ‘abnormal molecular pattern’ which allows HUSH to distinguish invading retroelements from host genes. Introns therefore provide a system which allows HUSH to discriminate ‘self’ from ‘non-self’ in the genome and identifies an unanticipated immune-surveillance system which protects the genome from ‘reverse genetic flow’ - thus revealing a new aspect of innate immunity
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