KRAS是人类癌症中最常见的突变致癌基因，突变型KRAS对胰腺导管腺癌（PDAC）负有超过90％的责任，这是最致命的癌症。在这里，我们展示了RNA聚合酶Ⅱ相关因子1复合物（PAF1C）对PDAC的存活具有特异性要求，但对正常成年胰腺细胞无影响。我们发现，PAF1C通过限制由突变型Kras驱动的增强子RNA（eRNA）和启动子上游转录本（PROMPTs）的过度累积来维持癌细胞的基因组稳定性。PAF1C的损失导致染色质上广泛转录产物长度的癌特异性延长和积累，同时伴随异常的R-loop形成和DNA损伤，进而触发细胞死亡。我们进一步证明，在肿瘤发生过程中，由Kras信号驱动的全局转录高活化为癌细胞对PAF1C的特定需求奠定了基础。我们的研究提供了增强子转录高活化在肿瘤发生过程中引起转录因子上瘾的整体机制的见解。版权所有©2023作者。由Elsevier Inc.发表。保留所有权利。

KRAS is the most commonly mutated oncogene in human cancer, and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II-associated factor 1 complex (PAF1C) is specifically required for survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining overaccumulation of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of pervasive transcripts on chromatin and concomitant aberrant R-loop formation and DNA damage, which, in turn, trigger cell death. We go on to demonstrate that the global transcriptional hyperactivation driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides insights into how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.