KEY RESOURCES TABLE.

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Rabbit polyclonal anti-SF3B1	Bethyl	Cat#A300–996A
Mouse monoclonal anti-Vinculin	Sigma	Cat#V9131
Mouse monoclonal anti-FLAG M2	Sigma	Cat#F1804
Mouse monoclonal anti-βActin	Sigma	Cat#A1978
Mouse monoclonal anti-αTubulin DM1A	Cell Signaling	Cat#3873
Rabbit polyclonal anti-H3	Millipore	Cat#07–690
Rabbit monoclonal anti-Cleaved Caspase 8 18C8	Cell Signaling	Cat#9496
Rabbit polyclonal anti-Cleaved Caspase 3	Cell Signaling	Cat#9661
Mouse monoclonal anti-RAN Clone 20	BD Biosciences	Cat#610340
Rabbit monoclonal anti-DR5 D4E9	Cell Signaling	Cat#8074
Rabbit polyclonal anti-TNFR2	Cell Signaling	Cat#3727
Rabbit monoclonal anti-DR4 D9S1R	Cell Signaling	Cat#42533
Rabbit monoclonal anti-TNFR1 C25C1	Cell Signaling	Cat#3736
Rabbit monoclonal anti-DR6 E8D21	Cell Signaling	Cat#93026
Rabbit monoclonal anti-cFLIP D5J1E	Cell Signaling	Cat#56343
Rabbit polyclonal anti-MAVS	Cell Signaling	Cat#3993
Mouse monoclonal J2 (anti-dsRNA)	Scicons	Cat#10010500
Alexa Fluor 488 goat anti-mouse IgG	Invitrogen	Cat#A11029
Alexa Fluor 594 goat anti-rabbit IgG	Invitrogen	Cat#A11012
Rabbit monoclonal anti-CD8a D4W2Z	Cell Signaling	Cat#98941
Bacterial and Virus Strains
N/A	N/A	N/A
Biological Samples
Syngeneic mouse tumors	Laboratory of Xiang H.-F. Zhang	N/A
Chemicals, Peptides, and Recombinant Proteins
H3B-8800	Seiler et al., 2018	N/A
SD6	Lagisetti et al., 2013	N/A
dTAG-51	Nabet et al., 2018	N/A
Z-VAD-FMK	R&D Systems	Cat#FMK001
Z-IETD-FMK	R&D Systems	Cat#FMK007
Z-AEVD-FMK	R&D Systems	Cat#FMK009
Z-LEHD-FMK	R&D Systems	Cat#FMK008
RNase III	Applied Biosystems	Cat#A2290
RNaseOne	Promega	Cat#M4261
SuperScript III	ThermoFisher Scientific	Cat#18080093
SYBR Select Master Mix	Applied Biosciences	Cat#4472908
Hoechst 33342, trihydrochloride, trihydrate	Life Technologies	Cat#H3570
Protease Inhibitor Cocktail	Roche	Cat#11836170001
Phosphatase Inhibitor Cocktail 2	Sigma	Cat#P5726
Clarity ECL Substrate	Bio-Rad	Cat#170–5060
Q5 High-Fidelity 2X MasterMix	New England Biosciences	Cat#M04292
RNasin Plus	Promega	Cat#N2111
Protein A Dynabeads	Invitrogen	Cat#10001D
Propidium Iodide	Sigma Aldrich	Cat#P4864
Critical Commercial Assays
RT2 Profiler PCR Array Human Antiviral Response	Qiagen	Cat#330321
Milliplex Human Cytokine/Chemokine Panel 1	MilliporeSigma	Cat#HCYTOMAG-60K
CellTiterGlo	Promega	Cat#G7570
Caspase-Glo 3/7	Promega	Cat#G8090
Caspase-Glo 8	Promega	Cat#G8200
Pierce BCA Protein Assay	Thermo Scientific	Cat#23225
Deposited Data
SUM159 SD6 RNA-Seq	This manuscript	GEO#GSE163414
LM2 SD6 RNA-Seq	This manuscript	GEO#GSE163411
SUM159 Cytoplasmic RNA-Seq	This manuscript	GEO#GSE163232
SUM159 J2 dsRIPseq	This manuscript	GEO#GSE163188
Syngeneic model RNA-Seq	This manuscript	GEO#GSE163181
TCGA RNA-Seq Data	Koboldt et al., 2012	dbGaP: phs000178.v10.p8; https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000178.v10.p8
TCGA RNA-Seq Clinical Data	The Cancer Genome Atlas Research Network	https://portal.gdc.cancer.gov/
Experimental Models: Cell Lines
Human: 293T	ATCC	Cat#ATCC CRL-3216
Human: SUM159 (female)	BioIVT	Cat#SUM-159PT
Human: MDA-MB-231-LM2 (female)	Minn et al., 2005	N/A
Human: HME1 (female)	Infinity	Cat#hTERT-HME1
Human: HME1 MYC-ER	Kessler et al., 2012	N/A
Human: SUM159 SF3B1−/− SF3B1-FKBP12F36V	This manuscript	N/A
Human: MDA-MB-231 (female)	ATCC	Cat#ATCC HTB-122
Human: BT549 (female)	ATCC	Cat#ATCC HTB-26
Human: SUM159 SF3B1WT	This manuscript	N/A
Human: SUM159 SF3B1R1074H	This manuscript	N/A
Human: MDA-MB-231-LM2 SF3B1WT	This manuscript	N/A
Human: MDA-MB-231-LM2 SF3B1R1074H	This manuscript	N/A
Mouse: p53−/− 2208L (female)	Laboratory of Xiang H.-F. Zhang	N/A
Mouse: p53−/− T11 (female)	Laboratory of Xiang H.-F. Zhang	N/A
Mouse: MMTV PyMT-M (female)	Laboratory of Xiang H.-F. Zhang	N/A
Mouse: AT3 (female)	Laboratory of Xiang H.-F. Zhang	N/A
Experimental Models: Organisms/Strains
Mouse: BALB/c AnNHsd (female)	Envigo	Cat#4701F
Mouse: C57BL/6J (female)	Jackson Laboratory	Cat#000664
Oligonucleotides
See Table S5 for shRNA sequences	Rousseaux et al., 2018	N/A
See Table S5 for siRNA sequences	ThermoFisher	https://www.thermofisher.com/us/en/home/life-science/rnai/synthetic-rnai-analysis/ambion-silencer-select-sirnas.html
See Table S6 for Primer Sequences used for RT-qPCR	Integrated Data Technologies	N/A
See Table S7 for smFISH probe sequences	Biosearch Technologies, Inc.	N/A
shRNA Genomic Amplification Forward Primer: TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGTAGTGAAGCCACAGATGTA	Integrated Data Technologies	N/A
shRNA Genomic Amplification Reverse Primer: GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGTATAAACGGTTGGTCTTCCAA	Integrated Data Technologies	N/A
sgRNA Control Sequence: GTCCTGGCAGGGCTGTGGTG	ThermoFisher	https://www.thermofisher.com/us/en/home/life-science/genome-editing/geneart-crispr/crispr-libraries/lentiarray-crispr-libraries.html
RNF128 sgRNA-1 Sequence: CACGAATTTCACGGTGCCCA	ThermoFisher	https://www.thermofisher.com/us/en/home/life-science/genome-editing/geneart-crispr/crispr-libraries/lentiarray-crispr-libraries.html
RNF128 sgRNA-2 Sequence: GAAATTCGTGTGCGGGTTAC	ThermoFisher	https://www.thermofisher.com/us/en/home/life-science/genome-editing/geneart-crispr/crispr-libraries/lentiarray-crispr-libraries.html
MAVS sgRNA-1 Sequence: GTACTTCATTGCGGCACTGA	ThermoFisher	https://www.thermofisher.com/us/en/home/life-science/genome-editing/geneart-crispr/crispr-libraries/lentiarray-crispr-libraries.html
MAVS sgRNA-2 Sequence: GGGTATTGAAGAGATGCCAG	ThermoFisher	https://www.thermofisher.com/us/en/home/life-science/genome-editing/geneart-crispr/crispr-libraries/lentiarray-crispr-libraries.html
SF3B1 crRNA-1 Sequence: AAGAUCGCCAAGACUCACGA	Dharmacon	Cat#CR-020061–01
Edit-tracrRNA	Dharmacon	Cat#U-002000
Recombinant DNA
pINDUCER20-Cas9	This manuscript	N/A
pHAGE-PGK-E2 Crimson	This manuscript	N/A
pHAGE-PGK-SF3B1-FKBP12F36V	This manuscript	N/A
pINDUCER20-SF3B1WT	This manuscript	N/A
pINDUCER20-SF3B1R1074H	This manuscript	N/A
pCW-Cas9	Wang et al., 2014	Addgene (Plasmid #50661)
pInducer20	Meerbrey et al., 2011	Addgene (Plasmid #44012)
Software and Algorithms
SAMtools (v1.4)	Li et al., 2009	https://github.com/samtools/
Hisat2 (v2.0.4)	Kim et al., 2015	https://daehwankimlab.github.io/hisat2/
Cufflinks (v2.2.1)	Trapnell et al., 2010	https://github.com/cole-trapnell-lab/cufflinks
FeatureCounts (v1.6.2)	Liao et al., 2014	http://subread.sourceforge.net/
MSigDB	Subramanian et al., 2005; Liberzon et al., 2011	http://www.broadinstitute.org/gsea/msigdb
Mouse gene expression pathways	Baderlab	http://baderlab.org/GeneSets
RefSeq Annotation	NCBI	https://www.ncbi.nlm.nih.gov/refseq/
DESeq2	Love et al., 2014	https://bioconductor.org/packages/release/bioc/html/DESeq2.html
Pysam	Li et al., 2009	https://github.com/pysam-developers/pysam
RepeatMasker (open-4.0.5)	Institute for Systems Biology	http://www.repeatmasker.org/
Metascape	Zhou et al., 2019	https://metascape.org/gp/index.html#/main/step1
Cutadapt	Martin, 2011	https://cutadapt.readthedocs.io/en/stable/index.html
Bowtie2	Langmead and Salzberg, 2012	https://github.com/BenLangmead/bowtie2
Meshes (v1.8.0)	Yu, 2018	https://bioconductor.org/packages/release/bioc/html/meshes.html
StringDB (v11.0)	Szklarczyk et al., 2018	https://string-db.org/
NIS-Element AR	Nikon	AR 4.30.01
ImageJ	NIH	https://imagej.nih.gov/ij/index.html
RNAfold	Institute for Theoretical Cehmistry	http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi
Adobe Photoshop	Adobe	N/A
ssGSEA	Barbie et al., 2009	https://github.com/broadinstitute/ssGSEA2.0
STAR aligner (v2.3.1)	Dobin et al., 2013	https://github.com/alexdobin/STAR
TCGAbiolinks	Colaprico et al., 2015	https://bioconductor.org/packages/release/bioc/html/TCGAbiolinks.html
Other
N/A	N/A	N/A