Carmen Espejo-Serrano, Catriona Aitken, Beatrice F Tan, Danielle G May, Rachel J Chrisopulos, Kyle J Roux, Jeroen AA Demmers, Samuel G Mackintosh, Joost Gribnau, Francisco Bustos, Cristina Gontan, Greg M Findlay

Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses

  • Health, Toxicology and Mutagenesis
  • Plant Science
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Ecology
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Protein ubiquitylation regulates key biological processes including transcription. This is exemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental gene expression by ubiquitylating the REX1 transcription factor and is mutated in an X-linked intellectual disability disorder. However, the precise mechanisms by which ubiquitylation drives specific transcriptional responses are not known. Here, we show that RNF12 is recruited to specific genomic locations via a consensus sequence motif, which enables co-localisation with REX1 substrate at gene promoters. Surprisingly, RNF12 chromatin recruitment is achieved via a non-catalytic basic region and comprises a previously unappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatin targeting is critical for REX1 ubiquitylation and downstream RNF12-dependent gene regulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1 axis and provide insight into mechanisms by which protein ubiquitylation enables programming of gene expression.

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