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- W4313374517 abstract "Abstract Ability of T cells to become activated and clonally expand during pathogen invasion is pivotal for the induction of protective immunity. Understanding how T cell receptor (TCR) signaling, cell cycle, and survival are coordinated could allow development of therapeutics designed to regulate the numbers of antigen-specific T cells. Activating mutations in Cul4b and its orthologue Cul4a are known to drive cell cycle and cancer development. Loss-of-function mutations in Cul4b have been identified in X-linked mental retardation patients. However, how Cul4b controls the function of primary T cell remains unknown. Using a novel proteomics screen, we identified Cul4b as highly active following TCR stimulation. Cul4b is expressed in naïve T cells but its levels and activity increased on TCR stimulation. We found that Cul4b was more abundant in T cells than Cul4a, and a significant proportion of Cul4b was associated with chromatin. To study the role of Cul4b in T cells we generated mice lacking Cul4b specifically in T cells. Loss of Cul4b impaired maintenance, proliferation and survival of activated T cells. Supporting this, Cul4b-deficient T cells were unable to expand and drive colitis. Cul4b deficient cells showed enrichment of cell cycle and DNA damage related pathways, with concomitant accumulation of pATM, P53, pCHK1, and γ-H2AX. In CD4 T cells, Cul4b preferentially associated with the substrate receptor DCAF1 to form an active CRL4B complex. Additionally, both Cul4b and DCAF1 were found to interact with proteins associated with DNA damage response and repair pathways. These findings demonstrate an essential role for Cul4b in promoting the rapid repair of damaged DNA to allow proliferation, survival and overall expansion of activated T cells." @default.
- W4313374517 created "2023-01-06" @default.
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- W4313374517 date "2020-05-01" @default.
- W4313374517 modified "2023-10-16" @default.
- W4313374517 title "Cul4b promotes DNA damage repair during T cell proliferation" @default.
- W4313374517 doi "https://doi.org/10.4049/jimmunol.204.supp.78.18" @default.
- W4313374517 hasPublicationYear "2020" @default.
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