Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome.

Pandey, A; Shen, C; Feng, S; Enosi Tuipulotu, D; Ngo, C; Liu, C; Kurera, M; Mathur, A; Venkataraman, S; Zhang, J; Talaulikar, D; Song, R; Wong, JJ-L; Teoh, N; Kaakoush, NO; Man, SM

Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome.

Pandey, A Shen, C Feng, S Enosi Tuipulotu, D

Ngo, C Liu, C Kurera, M Mathur, A Venkataraman, S Zhang, J Talaulikar, D Song, R Wong, JJ-L Teoh, N Kaakoush, NO Man, SM

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Publisher:: AMER ASSOC ADVANCEMENT SCIENCE
Publication Type:: Journal Article
Citation:: Sci Adv, 2024, 10, (4), pp. eadh3409
Issue Date:: 2024-01-26

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Field	Value	Language
dc.contributor.author	Pandey, A
dc.contributor.author	Shen, C
dc.contributor.author	Feng, S
dc.contributor.author	Enosi Tuipulotu, D https://orcid.org/0000-0002-6442-4633
dc.contributor.author	Ngo, C
dc.contributor.author	Liu, C
dc.contributor.author	Kurera, M
dc.contributor.author	Mathur, A
dc.contributor.author	Venkataraman, S
dc.contributor.author	Zhang, J
dc.contributor.author	Talaulikar, D
dc.contributor.author	Song, R
dc.contributor.author	Wong, JJ-L
dc.contributor.author	Teoh, N
dc.contributor.author	Kaakoush, NO
dc.contributor.author	Man, SM
dc.date.accessioned	2024-08-06T03:17:05Z
dc.date.available	2024-08-06T03:17:05Z
dc.date.issued	2024-01-26
dc.identifier.citation	Sci Adv, 2024, 10, (4), pp. eadh3409
dc.identifier.issn	2375-2548
dc.identifier.issn	2375-2548
dc.identifier.uri	http://hdl.handle.net/10453/180101
dc.description.abstract	The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. 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. Mechanistically, 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 and docking at Rab5+Rab7+ early-late endosomes. This Ku70-Ras-Raf signalosome activates the MEK-ERK pathways, leading to impaired activation of cell cycle proteins Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. We also identified the domains of Ku70, Ras, and Raf involved in activating the Ku70 signaling pathway. Therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartof	Sci Adv
dc.relation.isbasedon	10.1126/sciadv.adh3409
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	DNA
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Neoplasms
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neoplasms
dc.subject.mesh	DNA
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	DNA
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Neoplasms
dc.subject.mesh	Signal Transduction
dc.title	Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome.
dc.type	Journal Article
utslib.citation.volume	10
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-08-06T03:16:58Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	10
utslib.citation.issue	4

Abstract:

The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. 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. Mechanistically, 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 and docking at Rab5+Rab7+ early-late endosomes. This Ku70-Ras-Raf signalosome activates the MEK-ERK pathways, leading to impaired activation of cell cycle proteins Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. We also identified the domains of Ku70, Ras, and Raf involved in activating the Ku70 signaling pathway. Therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer.

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http://hdl.handle.net/10453/180101