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The translational repair pathway is a frequent synthetic lethal target in cancer

ABSTRACT: Synthetic lethality exploits the genetic vulnerabilities of cancer cells enabling, a targeted, precision approach to treat cancer. Synthetic lethal discovery approaches have led to clinical successes of PARP inhibitors and the progression of several next-generation therapeutic targets such as WRN, USP1, PKMYT1, POLQ, and PRMT5 into the clinic. To date, however, most discovery efforts in the synthetic lethal space have focused on DNA repair. Here, we show, for the first time in humans, a frequent synthetic lethal interaction between two complexes of the translational repair pathway, PELO/HBS1L and the superkiller (SKI) complex. In distinct genetic contexts, either in 9p21.3 (FOCAD) deleted or MSI-H tumors, we found that phenotypically destabilized SKI complex leads to dependence on the PELO/HBS1L ribosomal rescue complex. We estimate that 20% of all tumors have a destabilized SKI complex. The concomitant loss of PELO in a SKI destabilized tumor drives an unfolded protein stress response, cell cycle arrest, and robust tumor growth inhibition. Furthermore, we demonstrate that the loss of HBS1L phenocopies PELO loss, presenting a second potential therapeutic target within the rescue complex. Our results indicate that PELO/HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts and a significant patient population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261804 | GEO | 2024/10/14

REPOSITORIES: GEO

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Project description:Hbs1 has been established as a central component of the cell’s translational quality control pathways in both yeast and prokaryotic models; however, the functional characteristics of its human ortholog (Hbs1L) have not been well-defined. We recently reported a novel human phenotype resulting from a mutation in the critical coding region of the HBS1L gene characterized by facial dysmorphism, severe growth restriction, axial hypotonia, global developmental delay and retinal pigmentary deposits. Here we further characterize downstream effects of the human HBS1L mutation. HBS1L has three transcripts in humans, and RT-PCR demonstrated reduced mRNA levels corresponding with transcripts V1 and V2 whereas V3 expression was unchanged. Western blot analyses revealed HBS1L protein was absent in proband samples. Additionally, polysome profiling revealed an abnormal aggregation of 80S monosomes in patient cells under baseline conditions. RNASeq data corresponded to the patient phenotype, with biological process analysis showing skeletal system development and sensory development genes being most altered between patient and controls. Ribosomal sequencing demonstrated an increased translation efficiency of ribosomal RNA in Hbs1L-deficient fibroblasts, suggesting that there may be a compensatory increase in ribosome translation to accommodate the increased 80S monosome peak. Furthermore, lack of Hbs1L caused depletion of Pelota protein in both patient cells and mouse tissues, while PELO mRNA levels were unaffected. Inhibition of proteasomal function partially restored Pelota expression in human Hbs1L-deficient cells. We also describe a mouse model harboring a knockdown mutation in the murine Hbs1l gene that shared several of the phenotypic elements observed in the Hbs1L-deficient human including facial dysmorphism, growth restriction and retinal deposits. The Hbs1lKO mice similarly demonstrate diminished Pelota levels that were rescued by proteasome inhibition.

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The translational repair pathway is a frequent synthetic lethal target in cancer

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