Structure and functional mapping of the KRABāKAP1 repressor complex
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jats:titleAbstract</jats:title>jats:pTransposable elements are a genetic reservoir from which new genes and regulatory elements can emerge. However, expression of transposable elements can be pathogenic and is therefore tightly controlled. KRAB domainācontaining zinc finger proteins (KRABāZFPs) recruit the coārepressor KRABāassociated protein 1 (KAP1/TRIM28) to regulate many transposable elements, but how KRABāZFPs and KAP1 interact remains unclear. Here, we report the crystal structure of the KAP1 tripartite motif (TRIM) in complex with the KRAB domain from a human KRABāZFP, ZNF93. Structureāguided mutations in the KAP1āKRAB binding interface abolished repressive activity in an epigenetic transcriptional silencing assay. Deposition of H3K9me3 over thousands of loci is lost genomeāwide in cells expressing a KAP1 variant with mutations that abolish KRAB binding. Our work identifies and functionally validates the KRABāKAP1 molecular interface, which is critical for a central transcriptional control axis in vertebrates. In addition, the structureābased prediction of KAP1 recruitment efficiency will enable optimization of KRABs used in CRISPRi.</jats:p>
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1460-2075
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UKRIĀ¦Medical Research Council (MRC) (MR/S021604/1)
VetenskapsrĆ„det (VR) (2021ā03494)
Wellcome Trust (WT) (217191/Z/19/Z, 205833/Z/16/Z)