1. DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma.
- Author
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Taffoni C, Marines J, Chamma H, Guha S, Saccas M, Bouzid A, Valadao AC, Maghe C, Jardine J, Park MK, Polak K, De Martino M, Vanpouille-Box C, Del Rio M, Gongora C, Gavard J, Bidère N, Song MS, Pineau D, Hugnot JP, Kissa K, Fontenille L, Blanchet FP, Vila IK, and Laguette N
- Subjects
- Humans, Carcinogenesis, DNA metabolism, DNA Damage, DNA Repair, Immunity, Innate, Inflammation, Tumor Microenvironment, Glioblastoma genetics, Nucleotidyltransferases metabolism, DNA-Activated Protein Kinase metabolism
- Abstract
Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment in a glioblastoma model, a process that impairs early tumorigenesis but correlates with poor outcome in glioblastoma patients. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2023
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