PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma

• Published in: Nature communications Vol. 15; no. 1; p. 1446
• Main Authors: Gaballa, Abdallah, Gebhardt-Wolf, Anneli, Krenz, Bastian, Mattavelli, Greta, John, Mara, Cossa, Giacomo, Andreani, Silvia, Schülein-Völk, Christina, Montesinos, Francisco, Vidal, Raphael, Kastner, Carolin, Ade, Carsten P., Kneitz, Burkhard, Gasteiger, Georg, Gallant, Peter, Rosenfeldt, Mathias, Riedel, Angela, Eilers, Martin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/1; 14/34; 14/35; 38/23; 38/47; 45; 45/15; 45/22; 45/91; 631/250/2161; 631/67/1504/1713; 631/80/304; Adenocarcinoma; Cell activation; Damage; Deoxyribonucleic acid; Depletion; DNA; DNA biosynthesis; DNA damage; DNA repair; DNA-directed RNA polymerase; Elongation; Gene expression; Gene regulation; Genes; Humanities and Social Sciences; Immune evasion; Immunosurveillance; Lymphocytes T; Major histocompatibility complex; multidisciplinary; Myc protein; Pancreatic cancer; Pancreatic carcinoma; Ribonucleic acid; RNA; RNA polymerase; Science; Science (multidisciplinary); Surveillance; Survival; Transcription elongation; Yeast
• ISSN: 2041-1723; 2041-1723
• 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. MYC drives S-phase progression and immune invasion in pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms are not fully understood. Here, the authors show that the transcription elongation complex PAF1c controls the competition of different gene sets for RNA polymerase and elongation factors to regulate these MYC-associated mechanisms in PDAC.