GSE121960
Survival of cells with deregulated MYC requires UVSSA-dependent regulation of RNAPII dynamics
Cancer 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.