Structure-based peptide design identifies inhibitors of the dyskerin/dyskerin interaction in H/ACA ribonucleoproteins targeting brain tumour cell lines

Abstract

H/ACA ribonucleoparticles (RNPs) play key regulatory roles in ribosome biogenesis, splicing, and telomerase maintenance and their activities are enhanced in cancer cells. The central component of H/ACA RNPs is the enzyme dyskerin (DKC1). DKC1 has high expression in multiple tumour types, and contributes to cancer hallmarks, tumour growth and cellular immortalization. DKC1 mutations also cause dyskeratosis congenita, a premature-ageing syndrome characterised by hindered ribosome biogenesis and shortened telomeres. We leveraged genetic information to devise a strategy to generate dyskerin inhibitors. Mapping of DKC1 mutations on the cryo-EM structures of H/ACA RNP showed they alter the dyskerin/dyskerin protein-protein interaction in this complex. Based on this, we designed and synthesised peptides that inhibit dyskerin dimerization and developed in vitro protein assays demonstrating protein engagement and interaction inhibition. Lead peptides were tested in brain tumour cells (medulloblastoma and glioblastoma) and caused alterations in cell growth, viability, apoptosis, protein synthesis and snoRNA and telomerase RNA (hTERT) levels. These results suggest for the first time that inhibition of the protein interactions within the H/ACA RNP offers a new target for cancer treatment.