Towards understanding the role of the minor spliceosome in cancer

The minor spliceosome is tightly regulated to excise specialized introns called minor introns. One component, U6atac, plays a rate-limiting role. In the benign, normal state, transcripts with minor introns rapidly degrade or lead to mis-spliced transcripts. In cancer, cancer-promoting minor intron-containing proteins are produced. We propose 3 specific Aims to move towards novel therapies by fine-tuning minor splicing. – Reference source: Augspach et al. 2023, Molecular Cell (https://pubmed.ncbi.nlm.nih.gov/37295433/)

Rubin group  Prof. Mark A. Rubin MD

Genes are composed of coding units (exons), interspersed with non-coding regions called introns. The process of protein production involves splicing together exons while removing introns from the mRNA molecule. Evolution has given rise to a cellular apparatus called the spliceosome, responsible for carrying out this splicing process. 

Alternative splicing enables the generation of diverse protein isoforms from a single gene. Splicing is tightly regulated under normal physiological conditions. 

Our recent findings indicate that cancer cells use a specialized spliceosome, the so-called minor spliceosome, to increase cancer relevant mRNAs. As such cancer hijacks the minor intron-splicing machinery to enhance the expression of transcripts containing minor introns. Proteins encoded by those genes have been shown to activate critical cell survival pathways such as cell cycle regulation and DNA repair. 

Exploiting the reliance of cancer cells on minor intron-containing genes presents a novel therapeutic opportunity for targeting cancer. By inhibiting the minor spliceosome, we can selectively induce cell death in cancer cells while sparing healthy neighboring cells.