Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction

The tumor suppressor gene is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of itself, which frequently disrupts adjacent genes. Coincidental loss of -adjacent genes might impose vulnerabilities that could either...

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Bibliographic Details
Published in:eLife 2022-11, Vol.11
Main Authors: Winter, Jacob M, Fresenius, Heidi L, Cunningham, Corey N, Wei, Peng, Keys, Heather R, Berg, Jordan, Bott, Alex, Yadav, Tarun, Ryan, Jeremy, Sirohi, Deepika, Tripp, Sheryl R, Barta, Paige, Agarwal, Neeraj, Letai, Anthony, Sabatini, David M, Wohlever, Matthew L, Rutter, Jared
Format: Article
Language:English
Subjects:
Animals
Apoptosis
ATPases Associated with Diverse Cellular Activities - genetics
ATPases Associated with Diverse Cellular Activities - metabolism
BIM protein
Biochemistry and Chemical Biology
Cancer
Cancer Biology
Cells
Chromosome 10
Chromosome deletion
Cloning
CRISPR
Genes
Genomes
Histology
Homeostasis
Humans
Melanoma
Metastasis
Mice
Mitochondria
Mitochondria - metabolism
Mutation
Neoplasms - genetics
Prostate cancer
proteasome
Proteasome Endopeptidase Complex - metabolism
Proteasome inhibitors
Proteasomes
Proteins
PTEN Phosphohydrolase - metabolism
PTEN protein
synthetic lethality
Tumor suppressor genes
Tumors
Xenografts
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Description
Summary:The tumor suppressor gene is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of itself, which frequently disrupts adjacent genes. Coincidental loss of -adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here, we describe how the loss of , which is adjacent to and frequently co-deleted with , predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.82860