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KMID : 1034820210170020141
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Molecular & Cellular Toxicology
2021 Volume.17 No. 2 p.141 ~ p.149
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RepID-deficient cancer cells are sensitized to a drug targeting p97/VCP segregase
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Jang Sang-Min
Redon Christophe E.
Fu Haiqing
Indig Fred E.
Aladjem Mirit I.
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Abstract
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Background: The p97/valosin-containing protein (VCP) complex is a crucial factor for the segregation of ubiquitinated proteins in the DNA damage response and repair pathway.
Objective: We investigated whether blocking the p97/VCP function can inhibit the proliferation of RepID-deficient cancer cells using immunofluorescence, clonogenic survival assay, fluorescence-activated cell sorting, and immunoblotting.
Result: p97/VCP was recruited to chromatin and colocalized with DNA double-strand breaks in RepID-deficient cancer cells that undergo spontaneous DNA damage. Inhibition of p97/VCP induced death of RepID-depleted cancer cells. This study highlights the potential of targeting p97/VCP complex as an anticancer therapeutic approach.
Conclusion: Our results show that RepID is required to prevent excessive DNA damage at the endogenous levels. Localization of p97/VCP to DSB sites was induced based on spontaneous DNA damage in RepID-depleted cancer cells. Anticancer drugs targeting p97/VCP may be highly potent in RepID-deficient cells. Therefore, we suggest that p97/VCP inhibitors synergize with RepID depletion to kill cancer cells.
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KEYWORD
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p97/VCP segregase, RepID, DNA double-strand breaks, DNA damage response and repair, Cancer therapy
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