Table 1. Data and public resources used to infer the functions of DUB genes.

Resource	Description	Key Insights	Terms / abbreviations
DGE RNA-seq	High-throughput RNA-seq data collected for this study following knockout or inhibition of individual DUBs using CRISPR-Cas 9. 81 DUB knockouts (found in a commercial library) and 7 small molecules were characterized in biological replicate.	Transcriptional signatures acquired from cells in which individual DUBs are inactivated. This provides insight into potential gene function. Similarity between signatures of gene knockout and small molecules provides insight into small molecule selectivity.	3’DGE-seq: 3’ Digital Gene Expression, a type of high-throughput RNA-seq. Differentially Expressed (DE) gene: Gene with different level of expression across two samples as defined by a false discovery rate (FDR) adjusted P<0.05.
Connectivity Map (CMap)	A Broad Institute database of post-perturbation RNA-seq signatures generated from multiple cell lines following knockdown (RNAi or CRISPR-Cas 9), gene over-expression, or treatment of cells with small molecule drugs. Signatures in CMAP resource are comprised of 978 landmark genes measured using a Luminex bead-based assay. The expression of 11,350 genes is then inferred. Data are available for ~3000 genes and ~5000 small molecules.	Enables identification of genes that, when silenced with RNAi, or overexpressed, have similar transcriptional effects as a query L1000 or DGE-Seq signature. The effects of gene knockout/over-expression can be compared to the effects of drugs for mechanism of action studies.	Query mRNA profile: the transcriptomic signature that is used to query CMap and retrieve similar signatures. Tau score: a parameter that quantifies similarity between the query mRNA profile and CMap signatures (tau similarity is computed by counting the number of pairwise mismatches between two ranked lists). CMap recommends a threshold value for tau similarity scores of >90.
Dependency Map (DepMap)	A Broad Institute database of gene essentiality scored in >700 cancer cell lines based on genome-wide pooled CRISPR-Cas9 knockout screens. Dropout of specific Guide RNAs is used as a measure of essentiality.	Enables identification of genes that are essential for cell proliferation or survival in specific cell lines. Patterns of essentiality across cell line panels (the DepMap score) can be computed to identify genes potentially having related biological functions.	DepMap score – a measure of cell line dropout rate in a pooled genome-wide CRISPR screen (a gene with a dependency score <–0.5 is considered an essential gene in that cell line) Co-Dependency. Genes with similar DepMap scores are said to be co-dependent. In our study, we analyzed the top seven co-dependent genes, but similar data were obtained when more or fewer co-dependent genes were considered.
Cancer Cell Line Encyclopedia (CCLE) Proteomics	A Broad Institute database of baseline shotgun proteomics collected from CCLE cell lines. Data from ~375 cell lines and 12,000 proteins per line are available.	Protein co-expression across cell line panels provides insight into functional interactions: proteins in the same complex are often co-expressed to a significant degree across CCLE cell clines.	Co-expressed genes: correlation in protein abundance across cell lines with FDR <0.01 and |z-score|>2. These thresholds are set based on previous publications (Nusinow et al., 2020).
BioGRID	Protein-protein interaction database compiling interaction data from multiple sources. Protein interactions are measured using multiple physical assays including affinity capture MS, affinity capture western blotting, and assembly of reconstituted complexes from purified recombinant subunits in vitro.	Discovery of protein-protein interactions using a variety of methods that focus on physical interaction.	PPID: protein-protein interaction database.
IntAct	Protein-protein interaction database that compiles interaction data from multiple sources.	Discovery of protein-protein interactions using a variety of methods that focus on physical interaction.	PPID: protein-protein interaction database.
Pathway Commons	Protein-protein interaction database compiling interaction data from multiple sources.	Discovery of protein-protein interactions using a variety of methods that focus on physical interaction.	PPID: protein-protein interaction database.
NURSA	Physical interactions among proteins, particularly those involved in transcription.	Discovery of proteins that interact directly as determined by affinity capture mass spectrometry; approximately ~3000 IP assays are currently included.	PPID: protein-protein interaction database. NURSA: Nuclear Receptor Signaling Atlas