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
- Publisher:
- AMER ASSOC ADVANCEMENT SCIENCE
- Publication Type:
- Journal Article
- Citation:
- Sci Adv, 2024, 10, (4), pp. eadh3409
- Issue Date:
- 2024-01-26
Open Access
Copyright Clearance Process
- Recently Added
- In Progress
- Open Access
This item is open access.
Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Pandey, A | |
dc.contributor.author | Shen, C | |
dc.contributor.author | Feng, S | |
dc.contributor.author |
Enosi Tuipulotu, D |
|
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.
Please use this identifier to cite or link to this item:
Download statistics for the last 12 months
Not enough data to produce graph