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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE228800 | GEO | 2024/01/01

REPOSITORIES: GEO

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

Project description:In pancreatic ductal adenocarcinoma (PDAC), MYC is required for S-phase progression and escape from immune surveillance. Here we show that recruitment of the PAF1c transcription elongation complex to RNA polymerase depends on MYC and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for unperturbed proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with transcription-replication conflicts by being essential for expression of long DNA repair genes. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to restoration of immune surveillance. This occurs because CTR9 depletion releases RNA polymerase and the histone chaperone SPT6 from the body of long genes, promoting transcription of short genes that include MHC class-I genes. The data show that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

2024-01-01 | GSE228799 | GEO

PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma [RNA-seq]

2024-01-01 | GSE228797 | GEO

PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma [4sU-seq]

Project description: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.

2024-01-01 | GSE243701 | GEO