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Article Abstract
DNA damage repair is a critical biological process that maintains genomic integrity, and its dysregulation is closely related to tumorigenesis. To reveal the roles of mammalian target of rapamycin complex 2 (mTORC2) in DNA damage response (DDR), we investigated the temporal changes of cellular protein phosphorylation in mTORC2 deficient renal cancer cells in response to DNA double-strand break (DSB) induced by ionizing radiation (IR) using quantitative phosphoproteomics. The results showed that knockdown of Rictor, a specific component of mTORC2, induced profound changes in the dynamics of protein phosphorylation in response to IR. Intriguingly, the phosphorylation levels of multiple signaling molecules from the non-homologous end joining (NHEJ) pathway were affected by Rictor. Mechanistic study revealed that mTORC2 could regulate the spatiotemporal dynamics of p53 binding protein 1 (53BP1) in DDR. Rictor knockdown changed the phosphorylation of 53BP1 at multiple Ser/Thr sites. The efficiency of NHEJ was significantly reduced in Rictor deficient cells, and the maintenance of 53BP1 nuclear foci induced by IR was prolonged. Furthermore, mTORC2 modulated DSB repair through protein kinase B (PKB/Akt) and cyclin-dependent kinase 1 (CDK1). Finally, Rictor knockdown conferred hypersensitivity to IR and chemotherapeutic treatment in renal cancer cells, implying the potential use of the combination of mTORC2 inhibition with genotoxic therapy for renal cancer treatment.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356323 | PMC |
| http://dx.doi.org/10.1016/j.mcpro.2025.101035 | DOI Listing |
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