Sequence-specific RNA recognition drives Restrictor-mediated termination of extragenic transcription [HeLa__4sU-RNAseq]

Nevertheless, processive transcription is largely restricted to the small gene-containing fraction of the genome. A highly conserved and essential metazoan complex, Restrictor, composed of WDR82 and ZC3H4, restrains processive Pol II activity at thousands of extragenic transcription units, thus representing a critical enforcer of genome utilization.

However, because of the widespread recruitment of Restrictor to both genic and non-genic transcription sites, the identification of the mechanistic basis for its exquisite selectivity for extragenic transcription has remained elusive thus far. Here, we show that while WDR82 tethers Restrictor to sites of transcription initiation, the three C3H1-type zinc fingers of ZC3H4 make sequence-specific interactions with short motifs selectively enriched at the 5’ end of extragenic transcripts, with such interactions being required for transcription termination.