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Uncovering factors implicated in oncogenic NRAS modification by analyzing large scale functional genomic data sets Riyadh, Omer


The RAS proteins are a family of small GTPases responsible for cellular signal transduction. Oncogenic mutations in RAS family members (KRAS, HRAS, NRAS) are associated with specific cancers: for example, NRAS is a common driver in melanoma and leukemia. NRAS is trafficked by the addition of a 16-carbon lipid palmitate. The addition and removal of this palmitate are essential for localization and function, and blocking depalmitoylation reduces the proliferation of acute myeloid leukemia blasts in mice carrying oncogenic NRAS. The three isoforms of the alpha/beta hydrolase domain-containing 17 proteins, ABHD17A, ABHD17B and ABHD17C, can remove palmitate from NRAS when expressed in cultured cells. However, it is not known which ABHD17 isoform is most important for oncogenic NRAS activity or if these depalmitoylase enzymes work redundantly. To determine the relative importance of known depalmitoylation and palmitoylation enzymes for NRAS signaling, we used publicly available data from CRISPR-Cas9 functional genomic screens of cancer cell lines to predict genes essential for oncogenic NRAS-driven proliferation. In these screens, each gene is given a gene effect score that represents its essentiality in every cell line. Because KRAS and HRAS compensate for the loss of wild type NRAS, NRAS knockout specifically affects the subset of cell lines whose growth is driven by oncogenic NRAS. Thus, a gene essential for NRAS activity is expected to have a positively correlated gene essentiality score with that of NRAS in these cell lines. We further predict that enzymes required for NRAS palmitoylation and depalmitoylation will be important for the growth of cell lines dependent on oncogenic NRAS. To test these predictions, we separated cell lines into subsets based on the presence or absence of oncogenic NRAS alleles. We then computed Pearson correlation scores for all known genes with respect to NRAS in each subset. As predicted, NRAS lines were enriched for known components of the NRAS signalling pathway. We found that ABHD17B was a top hit in this analysis, and of all known depalmitoylase enzymes, only ABHD17B and ABHD13 had a gene essentiality score that was significantly positively correlated with that of oncogenic NRAS.

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