The UVSSA complex alleviates MYC-driven transcription stress.
The UVSSA complex alleviates MYC-driven transcription stress.
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DOI：
10.1083/jcb.201807163
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发表时间：
2021-02-01
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影响因子：
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通讯作者：
Gautier J
中科院分区：
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作者：
Sato M;Liebau RC;Liu Z;Liu L;Rabadan R;Gautier J
Sato等人证明MYC表达使MCF10A细胞对uvsa的下调敏感，因为它减轻了MYC依赖性转录过程中的压力。UVSSA是一种很有希望的攻击myc成瘾癌细胞的新靶点。癌细胞产生强烈的遗传依赖性，使其能够在致癌压力下存活。MYC是在大多数癌症中被激活的关键癌基因，识别相关的合成致死率或疾病可以为其活性和潜在的治疗策略提供重要线索。基于先前在表达MYC与雌激素受体片段融合的MCF10A细胞中进行的全基因组筛选，我们确定了uvsa，这是一个参与转录偶联修复的基因，当与MYC表达结合时，其敲低或敲除会降低细胞活力。MYC表达与uvsa下调之间的合成疾病相互作用与ATM/CHK2激活相关，表明基因组不稳定性增加。我们发现，通过降低RNA聚合酶II （RNAPII）活性，合成病相互作用减弱；然而，它独立于紫外线诱导的损伤修复，这表明在没有外源DNA损伤的情况下，UVSSA在调节RNAPII方面具有关键功能。支持这一假设的是，RNAPII ChIP-seq显示，RNAPII启动子占用myc依赖性的增加被UVSSA敲低而减少或消除，这表明在myc依赖性转录过程中，UVSSA影响了RNAPII的动力学。综上所述，我们的数据表明，在MYC成瘾期间，UVSSA复合物在支持MYC依赖性RNAPII动力学和维持细胞存活方面具有重要作用。虽然到目前为止，uvsa在调节RNAPII中的作用仅在紫外线诱导的DNA损伤修复的背景下被记录，但我们认为它的活性也需要应对癌基因激活诱导的转录变化。
Sato et al. demonstrate that MYC expression renders MCF10A cells sensitive to down-regulation of UVSSA, as it alleviates stress during MYC-dependent transcription. UVSSA is a promising novel target for attacking MYC-addicted cancer cells. 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 or sickness can provide important clues about its activity and potential therapeutic strategies. On the basis of previously conducted genome-wide screenings in MCF10A cells expressing MYC fused to an estrogen receptor fragment, we identified UVSSA, a gene involved in transcription-coupled repair, whose knockdown or knockout decreased cell viability when combined with MYC expression. Synthetic sick interactions between MYC expression and UVSSA down-regulation correlated with ATM/CHK2 activation, suggesting increased genome instability. We show that the synthetic sick interaction is diminished by attenuating RNA polymerase II (RNAPII) activity; yet, it is independent of UV-induced damage repair, suggesting that UVSSA has a critical function in regulating RNAPII in the absence of exogenous DNA damage. Supporting this hypothesis, RNAPII ChIP-seq revealed that MYC-dependent increases in RNAPII promoter occupancy are reduced or abrogated by UVSSA knockdown, suggesting that UVSSA influences RNAPII dynamics during MYC-dependent transcription. Taken together, our data show that the UVSSA complex has a significant function in supporting MYC-dependent RNAPII dynamics and maintaining cell survival during MYC addiction. While the role of UVSSA in regulating RNAPII has been documented thus far only in the context of UV-induced DNA damage repair, we propose that its activity is also required to cope with transcriptional changes induced by oncogene activation.