Department of Biochemistry and Molecular Biologyy, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.
Mildred Scheel Early Career Center, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
Nat Commun. 2024 Feb 16;15(1):1446. doi: 10.1038/s41467-024-45760-8.
In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.
在胰腺导管腺癌（PDAC）中，内源性 MYC 是 S 期进展和逃避免疫监视所必需的。在这里，我们表明 PDAC 细胞中的 MYC 需要 PAF1c 转录延伸复合物招募到 RNA 聚合酶，并且 PAF1c 亚基 CTR9 的耗竭使携带 PDAC 的小鼠能够长期存活。PAF1c 对于正常增殖和 MYC 靶基因的调节在很大程度上是可有可无的。相反，PAF1c 通过对涉及复制和 DNA 修复的长基因的表达是必需的，从而限制与 S 期进展相关的 DNA 损伤。令人惊讶的是，CTR9 耗竭赋予的生存益处不是由于 DNA 损伤，而是由于 T 细胞激活和恢复免疫监视。这是因为 CTR9 耗竭将 RNA 聚合酶和延伸因子从长基因的主体中释放出来，并促进包括 MHC 类 I 基因在内的短基因的转录。这些数据表明，功能不同的基因集争夺延伸因子，并将 MYC 驱动的 S 期进展直接与肿瘤免疫逃逸联系起来。
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