The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription. Second, ARF targets the RUNX family transcription factor 1 (RUNX1) to selectively tune gene transcription. Consistently, ARF loss triggers RUNX1- and PAF1c-dependent transcriptional activation of pro-growth ligands (growth differentiation factor/bone morphogenetic protein [GDF/BMP]), promoting a cell-intrinsic GDF/BMP-Smad1/5 axis that aberrantly induce cell growth. Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.

中文翻译：

---

ARF 改变 PAF1 复合物的完整性，在 p53 缺失时选择性地抑制致癌转录程序


聚合酶相关因子 1 （PAF1） 复合物 （PAF1c） 在延伸步骤促进 RNA 聚合酶 II （RNA Pol II） 转录;然而，在细胞命运转换过程中如何选择性调节 PAF1c 转录活性仍然知之甚少。在这里，我们揭示了替代阅读框 （ARF） 肿瘤抑制因子在两个水平上起作用，以抑制小鼠细胞中 p53 丢失时 PAF1c 依赖性的致癌转录程序。首先，ARF 组装成同源寡聚体以结合 PAF1 亚基以促进 PAF1c 分解，从而抑制 PAF1c 与 RNA Pol II 的相互作用和 PAF1c 依赖性转录。其次，ARF 靶向 RUNX 家族转录因子 1 （RUNX1） 以选择性调节基因转录。始终如一，ARF 缺失触发促生长配体 （生长分化因子/骨形态发生蛋白 [GDF/BMP]）的 RUNX1 和 PAF1c 依赖性转录激活，促进细胞内在的 GDF/BMP-Smad1/5 轴异常诱导细胞生长。值得注意的是，GDF/BMP 信号传导的药理学失活和 RUNX1 的遗传扰动显着减弱了由 p53 和 ARF 双重缺失介导的细胞增殖，具有治疗效用。我们的数据强调了选择性 ARF 介导的肿瘤抑制功能通过通用转录调节因子的重要性。