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Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway.

ABSTRACT: Blood cells are challenged by intrinsic and exogenous stress that may result in many types of damage to DNA. As a major participant in cell-mediated immunity in blood, T lymphocytes are maintained in their quiescent (resting) state for most of their lives and switch to the proliferating state once stimulated. How resting and stimulated T cells address DNA damage remains largely unknown. Here, we report that while different types of DNA damage are efficiently repaired in stimulated T cells, they result in massive apoptosis of resting T cells. Mechanistically, DNA damage in resting T cells activates the ATM/ATR/DNA-PKcs signaling pathway but fails to induce the formation of ?H2AX and 53BP1 foci, leading to unrepaired DNA damage that activates apoptosis in a p53-independent but JNK/p73-dependent manner. Mice challenged with high DNA damage stress display far fewer T cells in peripheral blood, lymph nodes, and spleens. Collectively, these results reveal that resting T cells are hypersensitive to DNA damage due to defects in DNA damage repair mechanisms. These findings provide new insight into T-cell function and maintenance of immunity under highly stressed conditions.

SUBMITTER: Hu Q

PROVIDER: S-EPMC5981309 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway.

Hu Qian Q Xie Yujie Y Ge Yuanlong Y Nie Xin X Tao Jun J Zhao Yong Y

Cell death & disease 20180531 6

Blood cells are challenged by intrinsic and exogenous stress that may result in many types of damage to DNA. As a major participant in cell-mediated immunity in blood, T lymphocytes are maintained in their quiescent (resting) state for most of their lives and switch to the proliferating state once stimulated. How resting and stimulated T cells address DNA damage remains largely unknown. Here, we report that while different types of DNA damage are efficiently repaired in stimulated T cells, they ...[more]

PMID: 29855463

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Project description:BACKGROUND:Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown. METHODS:We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE-/- mice. RESULTS:Human plaque VSMCs showed defective nuclear 8oxoG repair, associated with reduced acetylation of OGG1. OGG1 was a key regulatory enzyme of 8oxoG repair in VSMCs, and its acetylation was crucial to its repair function through regulation of protein stability and expression. p300 and sirtuin 1 were identified as the OGG1 acetyltransferase and deacetylase regulators, respectively, and both proteins interacted with OGG1 and regulated OGG1 acetylation at endogenous levels. However, p300 levels were decreased in human plaque VSMCs and in response to oxidative stress, suggesting that reactive oxygen species-induced regulation of OGG1 acetylation could be caused by reactive oxygen species-induced decrease in p300 expression. We generated mice that express VSMC-restricted OGG1 or an acetylation defective version (SM22?-OGG1 and SM22?-OGG1K-R mice) and crossed them with ApoE-/- mice. We also studied ApoE-/- mice deficient in OGG1 (OGG1-/-). OGG1-/- mice showed increased 8oxoG in vivo and increased atherosclerosis, whereas mice expressing VSMC-specific OGG1 but not the acetylation mutant OGG1K-R showed markedly reduced intracellular 8oxoG and reduced atherosclerosis. VSMC OGG1 reduced telomere 8oxoG accumulation, DNA strand breaks, cell death and senescence after oxidant stress, and activation of proinflammatory pathways. CONCLUSIONS:We identify defective 8oxoG base excision repair in human atherosclerotic plaque VSMCs, OGG1 as a major 8oxoG repair enzyme in VSMCs, and p300/sirtuin 1 as major regulators of OGG1 through acetylation/deacetylation. Reducing oxidative damage by rescuing OGG1 activity reduces plaque development, indicating the detrimental effects of 8oxoG on VSMC function.

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Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway.

Publications

Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway.

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