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

Abdallah Gaballa, Anneli Gebhardt-Wolf, Bastian Krenz, Greta Mattavelli, Mara John, Giacomo Cossa, Silvia Andreani, Christina Schülein-Völk, Francisco Montesinos, Raphael Vidal, Carolin Kastner, Carsten P. Ade, Burkhard Kneitz, Georg Gasteiger, Peter Gallant, Mathias Rosenfeldt, Angela Riedel and Martin Eilers ()
Additional contact information
Abdallah Gaballa: Am Hubland
Anneli Gebhardt-Wolf: Am Hubland
Bastian Krenz: Am Hubland
Greta Mattavelli: University Hospital Würzburg, Josef-Schneider-Str. 2
Mara John: University Hospital Würzburg, Josef-Schneider-Str. 2
Giacomo Cossa: Am Hubland
Silvia Andreani: Am Hubland
Christina Schülein-Völk: Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland
Francisco Montesinos: Am Hubland
Raphael Vidal: Am Hubland
Carolin Kastner: University Hospital Würzburg, Josef-Schneider-Str. 2
Carsten P. Ade: Am Hubland
Burkhard Kneitz: University Hospital Würzburg, Josef-Schneider-Str. 2
Georg Gasteiger: Max Planck Research Group, Julius Maximilian University Würzburg, Versbacher Str. 9
Peter Gallant: Am Hubland
Mathias Rosenfeldt: Julius Maximilian University Würzburg, Josef-Schneider-Str. 2
Angela Riedel: University Hospital Würzburg, Josef-Schneider-Str. 2
Martin Eilers: Am Hubland

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45760-8

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