Measurement of UVB-Induced DNA damage and its consequences in models of immunosuppression

Yarosh, Daniel B.; Boumakis, Stavroula; Brown, Anne B.; Canning, Matthew T.; Galvin, Jason; Both, Dawn; Kraus, Eliyahu; O’Connor, Adrienne; Brown, David A.

doi:10.1016/s1046-2023(02)00209-8

Cited by 47 publications

(28 citation statements)

References 66 publications

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“…As discussed previously, TLR4 2/2 and MyD88 2/2 cells do not undergo a typical apoptotic cell death after UVR; instead, they die by necroptosis (44). This observation supports our findings that MyD88 2/2 mice are resistant to UV immunosuppression because the apoptotic fragments released during classical UV-induced cell death are known to contribute to UV-induced systemic immunosuppression.…”

Section: Discussionsupporting

confidence: 92%

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Harberts

Zhou

Fishelevich

et al. 2015

The Journal of Immunology

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UV radiation (UVR) induces DNA damage, leading to the accumulation of mutations in epidermal keratinocytes and immunosuppression, which contribute to the development of nonmelanoma skin cancer. We reported previously that the TLR4–MyD88 signaling axis is necessary for UV-induced apoptosis. In the dinitrofluorobenzene contact hypersensitivity model, UV-irradiated MyD88-deficient (MyD88−/−) C57BL/6 mice had intact ear swelling, exaggerated inflammation, and higher levels of dinitrofluorobenzene-specific IgG2a compared with wild-type (WT) mice. Even with normal UV-induced, dendritic cell migration, DNA damage in the local lymph nodes was less pronounced in MyD88−/− mice compared with WT mice. Cultured, UV-irradiated WT APCs showed cleavage (inactivation) of the DNA damage–recognition molecule PARP, whereas PARP persisted in MyD88−/− and TLR4−/− APCs. Epidermal DNA from in vivo UV-irradiated MyD88−/− mice had an increased resolution rate of cyclobutane pyrimidine dimers. Both in vitro treatment of MyD88−/− APCs with and intradermal in vivo injections of PARP inhibitor, PJ-34, caused WT-level cyclobutane pyrimidine dimer repair. Lymphoblasts deficient in DNA repair (derived from a xeroderma pigmentosum group A patient) failed to augment DNA repair after MyD88 knockdown after UVR, in contrast to lymphoblasts from a healthy control. These data suggest that interference with the TLR4/MyD88 pathway may be a useful tool in promoting DNA repair and maintaining immune responses following UVR-induced damage.

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Section: Discussionsupporting

confidence: 92%

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Harberts

Zhou

Fishelevich

et al. 2015

The Journal of Immunology

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“…Antibodies against the cyclobutane form of thymine dimers have been used for many years. [39][40][41] Fixed cells or skin samples are first treated by the anti-thymidine dimer antibody and then by a fluorescent anti (anti-thymidine dimer) to allow the detection of DNA damage in the nucleus.…”

Section: Specific Detection By Antibodiesmentioning

confidence: 99%

Skin DNA photodamage and its biological consequences

Marrot

Meunier

2008

Journal of the American Academy of Dermatology

294

226

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“…Bcl-2 as a regulator of apoptosis is believed to alter mitochondrial permeability transition through its ion channel activity and inhibits the release of both cytochrome c and apoptosis-inducing factor from the mitochondria, thereby promoting cell survival. Importantly, it has been reported that damage to DNA results in activation of damage response pathways in human epidermal keratinocytes (37). The signal derived from DNA damage to the activation of these response pathways is mediated by mTOR.…”

Section: Tablementioning

confidence: 99%

Glucose-stimulated DNA Synthesis through Mammalian Target of Rapamycin (mTOR) Is Regulated by KATP Channels

Kwon

Marshall

Liu

et al. 2006

Journal of Biological Chemistry

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The aim of this study was to define metabolic signaling pathways that mediate DNA synthesis and cell cycle progression in adult rodent islets to devise strategies to enhance survival, growth, and proliferation. Since previous studies indicated that glucose-stimulated activation of mammalian target of rapamycin (mTOR) 3 H]thymidine incorporation without altering S phase accumulation under chronic elevated glucose, this increase in DNA synthesis also appears to be primarily related to an arrest in S phase and not cell proliferation.Both types 1 and 2 diabetes result from the inability of pancreatic ␤-cells to secrete sufficient amounts of insulin to maintain normal glucose homeostasis due to an acquired secretory defect and/or inadequate ␤-cell mass. Increased metabolic demands or stress responses that exert a positive effect on ␤-cell mass include obesity, pregnancy, partial pancreatectomy, or chronic glucose exposure. ␤-Cell mass is regulated by cellular mechanisms that include replication, neogenesis, hypertrophy, and apoptosis (1, 2). Recent studies have emphasized the importance of the proliferative capacity of existing adult ␤-cells as a major source of new ␤-cells during adult life that may significantly contribute to the maintenance of ␤-cell mass (3).Mammalian target of rapamycin (mTOR) 2 is a serine/threonine protein kinase that integrates signals derived from growth factors and nutrients to regulate cell growth and proliferation through the regulatory proteins 70-kDa ribosomal protein S6 kinase (S6K1) and the eukaryotic initiation factor 4E-binding protein-1 (4EBP1). This signaling cascade stimulates protein translation and increases the capacity of the ribosomal protein machinery necessary for the onset of DNA synthesis (4, 5). Our previous studies have demonstrated that glucose robustly activates mTOR/S6K1/4EBP1 in an amino acid-dependent manner via its metabolism in both rodent and human islets. Glucose and amino acids, especially leucine and glutamate, are the most prominent activators of mTOR in islets, possibly through ATP production mediated by mitochondrial metabolism (6 -9). Insulin secreted by the ␤-cell and growth factors also provide input to mTOR through the insulin signaling cascade to Akt (6). Akt may directly activate mTOR but also has been shown to inhibit the tumor suppressor proteins TSC1/2. These proteins are activated by AMP-dependent protein kinase that is regulated by the ATP/AMP ratio. Rapamycin specifically inhibits mTOR activation and signaling to 4EBP1 and S6K1. Recent reports have demonstrated a negative feedback pathway from chronically stimulated mTOR to IRS2 that inhibits the insulin signaling pathway (10). Apparently, this negative feedback to IRS2 does not reduce nutrient-stimulated mTOR activation in the ␤-cell as S6K1 remains fully activated during a 4-or 6-day exposure to elevated glucose (7), although other IRS2-dependent pathways may be inhibited.Our previous studies demonstrated that the majority of glucose-stimulated [3 H]thymidine incorporation by rodent islets...

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Measurement of UVB-Induced DNA damage and its consequences in models of immunosuppression

Cited by 47 publications

References 66 publications

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Skin DNA photodamage and its biological consequences

Glucose-stimulated DNA Synthesis through Mammalian Target of Rapamycin (mTOR) Is Regulated by KATP Channels

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