Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome

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Presentation Time: 01:30 PM - 01:45 PM
Abstract ID: 4815 - A

Presenting Author:
Abhimanu Pandey , PostDoc Fellow at Australian Natl. Univ.

Abstract:

Pattern-recognition receptors are critical in the host defence against infectious diseases and cancer. DNA is the genetic code of life but also represents a form of microbial or damage-associated signal which can induce an immune response. Central to immune surveillance are the cytoplasmic DNA sensors that respond to microbial or endogenous DNA liberated from microbes or damaged and/or dying host cells. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer. The effect of Ku70 on attenuating intestinal cancer was independent of the role of Ku70 in DNA repair, and the production of inflammatory markers and interferons. Instead, Ku70 translocates from the nucleus into the cytoplasm where it binds to cytosolic DNA and interacts with the GTPase Ras and the kinase Raf, forming a tripartite protein complex that docks at Rab5+Rab7+ early- late endosomes. We identified that the ⍺/β domain and the C-terminal domain of Ku70 interact with the GTPase domain of Ras, whereas the C-terminal domain of Ku70 interacts with the conserved region 2 of Raf. The Ku70-Ras-Raf signalosome activates the MEK-ERK signalling pathway, leading to impaired activation of cell cycle proteins, Chk2, Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. These findings suggest that therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer.