DNA-directed RNA polymerase II and spliceosome complex (Pol II/Spliceosome)

The Host RNA Polymerase II and canonical pre-mRNA splicing/backsplicing machinery represents the integrated system responsible for the synthesis and processing of eukaryotic transcripts. RNA Polymerase II (Pol II) is the multi-subunit enzyme that transcribes DNA into pre-messenger RNA (pre-mRNA), while the spliceosome—a dynamic complex of small nuclear ribonucleoproteins (snRNPs)—removes non-coding introns through canonical splicing [1, 2]. This same machinery can also catalyze backsplicing, a process where a 5' splice site is joined to an upstream 3' splice site to generate circular RNAs (circRNAs), which play diverse roles in gene regulation [3]. In many viral infections, such as those caused by SARS-CoV-2 or Influenza, the virus hijacks or disrupts these host processes to suppress the host's antiviral response and prioritize the production of viral proteins [4]. Therapeutically, this machinery is targeted primarily in oncology; for instance, small molecules like H3B-8800 modulate the SF3B1 subunit of the spliceosome to treat hematologic malignancies harboring splicing factor mutations [5]. However, because these processes are essential for the survival of all eukaryotic cells, drugs targeting this machinery often face challenges related to systemic toxicity and a narrow therapeutic index [6].

Other names

RNA Pol IIRNAP IISpliceosomeBacksplicing machineryTranscription-splicing complexHost transcription machinery

Inhibition of RNA Polymerase II-mediated transcription elongation and modulation of the SF3B complex within the spliceosome to disrupt pre-mRNA processing and circular RNA formation.