Schematic of QC step testing scanning competence of pre-40S ribosome. (A) QC mechanisms check for proper incorporation of RPs and folding of 18S rRNA in the ribosomal head before forming the scanning competent 80S-like ribosome. Failure to pass QC results in turnover of these pre-40S intermediates. (B) On the other hand, bypass of QC by using a weakly binding Enp1 mutant (yellow star) allows pre-40S with misfolded rRNA and mispositioned RPs to form 80S-like ribosomes that are eventually released into the translating pool, where they will have defects in start codon selection (Huang et al., 2020). (C) Structure of the human pre-40S ribosomal subunit (gray) bound by BYSL (yellow), LTV1 (orange), and RIOK2 (red; PDB accession no. 6G18; Ameismeier et al., 2018). Colored spheres indicate residues in BYSL (Enp1) that are mutated in cancer and are predicted to bypass QC (dark blue spheres indicate point mutations in residues R303 and P318, while cyan spheres mark nonsense mutations at Y265 and R267 that produce truncated Enp1 protein). Inset on the left has RPs removed for clarity (TCGA www.cancer.gov/tcga, cBioPortal www.cbioportal.org).