Fig. 7: CDS2 dosage and catalytic activity govern synthetic lethality.
a, The relationship between CDS1 expression and ΔCDS2 lethality. Deciles for cancer cell line CDS1 expression were plotted against ΔCDS2 lethality using DepMap data, with variation in ΔCDS2 lethality indicated by the interquartile range. A sigmoid curve was fitted through the CDS1 expression deciles with r = 0.998. Hill’s equation yielded a log2(TPM + 0.0625) of 1.273 as the level of CDS1 expression, with 50% of maximum synthetic lethality among the cancer cell line collection (dashed line). For the totals above and below this level, numbers and percentages are shown on top, together with a histogram of the cancer cell line distribution. n = 913 cancer cell lines (DepMap). b, Graph depicting quantification of the 10-d synthetic lethality in BLM using the method for quantifying synthetic lethality with ectopic CDS1 or GFP expression described in Fig. 2f. Two-way ANOVA followed by Šidák’s test was used. n = 3 replicates for 1 cancer cell line for 3 shCDS2. c, Tumor growth after subcutaneous inoculation of control and CDS2-perturbed BLM melanoma cells. Two-way ANOVA was used (n = 9 NOD-scid Il2rγ-null mice per group for 1 cancer cell line). d, For two CDS1-negative melanoma cancer cell lines CDS1, GFP (control), CDS2–GFP or CDS2–GFP Asp384Ala was ectopically expressed and the 14-d ΔCDS2 lethality was determined using tracker cells (Fig. 2c). Two-way ANOVA followed by Šidák’s test was used. n = 3 replicates for 2 cancer cell lines. The CDS2–GFP and CDS2–GFP Asp384Ala cell line variants were each generated in duplicate via independent transductions (no. 1, 2). ΔCDS2 lethality in CDS1 or GFP variants was replicated in one independent experiment for SK-MEL-2 (Fig. 2e) and two independent experiments for BLM (Fig. 2f: in vitro; Fig. 2h: in vivo). e, A diagram summarizing the mechanistic aspects of CDS1–CDS2 synthetic lethality. On the left, upregulated cholesterol proteins are listed. On the right, buildup of the substrate lipids (PA, DAG) and of the lipid droplet lipids (CEs, TAGs) and depletion of the product PI is indicated. In b–d: ***P < 0.001.
