ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/004/SRR8133464/SRR8133464.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/000/SRR8133470/SRR8133470.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/008/SRR8133468/SRR8133468.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/006/SRR8133456/SRR8133456.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/007/SRR8133457/SRR8133457.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/000/SRR8133460/SRR8133460.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/002/SRR8133462/SRR8133462.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/009/SRR8133459/SRR8133459.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/005/SRR8133465/SRR8133465.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/007/SRR8133467/SRR8133467.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/001/SRR8133471/SRR8133471.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/003/SRR8133463/SRR8133463.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/009/SRR8133469/SRR8133469.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/008/SRR8133458/SRR8133458.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/006/SRR8133466/SRR8133466.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR813/001/SRR8133461/SRR8133461.fastq.gzprimaryOK200GenomicsThe Rabadan Lab, Systems Biology, Columbia universityhttps://www.ebi.ac.uk/ena/browser/view/PRJNA501802Homo sapiensxref:PubMed:33404608Cancer cells develop strong genetic dependencies enabling survival under oncogenic stress. MYC is a key oncogene activated across most cancers, and identifying associated synthetic lethality can provide important clues about its activity and potential therapeutic strategies. Based on previously conducted genome-wide screenings we identified UVSSA, a gene involved in transcription-coupled repair whose knockdown decreased cell viability when combined with MYC activation. Synthetic lethal interactions between MYC expression and UVSSA loss correlated with ATM/CHK2 activation, suggesting increased genome instability. We show that although the synthetic lethal interaction was diminished by attenuating RNA polymerase II (RNAPII) activity, it becomes independent of UV-induced damage repair, suggesting that UVSSA has a critical function in regulating transcription in the absence of exogenous DNA damage. Supporting this hypothesis, RNAPII-ChIP-seq revealed that MYC-dependent increase in RNAPII promoter occupancy, as well as RNAPII stalling, is reduced or abrogated by UVSSA knockdown, suggesting that UVSSA negatively regulates MYC-dependent transcription. Taken together, our data shows that the UVSSA complex is required to limit MYC-dependent transcription stress and to maintain cell survival. While the role of UVSSA in regulating RNAPII dynamics has only been documented thus far in the context of UV-induced DNA damage repair, we propose that its activity is also required to cope with transcription stress induced by oncogene activation. Overall design: Examination of chromatin-bound RNAPII levels at actively transcribing genes under 4 conditions: CONTROL, MYC-ER ONLY, shUVSSA ONLY, and MYC+shUVSSA.ENAfalseSurvival of cells with deregulated MYC requires UVSSA-dependent regulation of RNAPII dynamicsSurvival of cells with deregulated MYC requires UVSSA-dependent regulation of RNAPII dynamics2025-09-242020-11-02PRJNA501802GSE121960960633404608