Caffeine and human DNA metabolism: the magic and the mystery

Kaufmann, William K.; Heffernan, Timothy P.; Beaulieu, Lea M.; Doherty, Sharon C.; Frank, Alexandra R.; Zhou, Yingchun; Bryant, Miriam F.; Zhou, Tong; Luche, Douglas D.; Nikolaishvili-Feinberg, Nana; Simpson, Dennis A.; Cordeiro‐Stone, Marila

doi:10.1016/j.mrfmmm.2003.08.012

Cited by 85 publications

(66 citation statements)

References 57 publications

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“…We therefore examined the ability of T cells from C57BL/6 mice to proliferate in response to anti-CD3 and anti-CD28 Abs in the presence of caffeine, which is known to inhibit Atm. Caffeine concentrations of 1 mM inhibit Atm, but not ATR function in vitro and caffeine concentrations of 3 mM inhibit both Atm and ATR function by 50% (22,23). Stimulation of C57BL/6 T cells with anti-CD3 and anti-CD28 in the presence of caffeine induced T cell apoptosis (Fig.…”

Section: Resultsmentioning

confidence: 93%

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Bagley

Singh

Iacomini

2007

The Journal of Immunology

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Mutations in the gene encoding ataxia-telangiectasia (A-T) mutated (Atm) cause the disease A-T, characterized by immunodeficiency, the molecular basis of which is not known. Following stimulation through the TCR, Atm-deficient T cells and normal T cells in which Atm is inhibited undergo apoptosis rather than proliferation. Apoptosis is prevented by scavenging reactive oxygen species (ROS) during activation. Atm therefore plays a critical role in T cell proliferation by regulating responses to ROS generated following T cell activation. The inability of Atm-deficient T cells to control responses to ROS is therefore the molecular basis of immunodeficiency associated with A-T.

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Section: Resultsmentioning

confidence: 93%

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Bagley

Singh

Iacomini

2007

The Journal of Immunology

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“…To explore this possibility, we tested whether cell cycle arrest could be prevented by the addition of caffeine. Although caffeine has pleiotropic effects on cells, it is an effective inhibitor of ATM and ATR and has been used to abrogate DNA damage checkpoints in a variety of organisms, including Tetrahymena (24,26,48). For example, the addition of caffeine to Tetrahymena cells that have suffered DNA damage during S phase abrogates the intra-S-phase checkpoint and allows the cells to resume proliferation (48).…”

Section: Resultsmentioning

confidence: 99%

Tetrahymena POT1a Regulates Telomere Length and Prevents Activation of a Cell CycleCheckpoint

Jacob

Lescasse

Linger

et al. 2007

Molecular and Cellular Biology

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The POT1/TEBP telomere proteins are a group of single-stranded DNA (ssDNA)-binding proteins that have long been assumed to protect the G overhang on the telomeric 3 strand. We have found that the Tetrahymena thermophila genome contains two POT1 gene homologs, POT1a and POT1b. The POT1a gene is essential, but POT1b is not. We have generated a conditional POT1a cell line and shown that POT1a depletion results in a monster cell phenotype and growth arrest. However, G-overhang structure is essentially unchanged, indicating that POT1a is not required for overhang protection. In contrast, POT1a is required for telomere length regulation. After POT1a depletion, most telomeres elongate by 400 to 500 bp, but some increase by up to 10 kb. This elongation occurs in the absence of further cell division. The growth arrest caused by POT1a depletion can be reversed by reexpression of POT1a or addition of caffeine. Thus, POT1a is required to prevent a cell cycle checkpoint that is most likely mediated by ATM or ATR (ATM and ATR are protein kinases of the PI-3 protein kinase-like family). Our findings indicate that the essential function of POT1a is to prevent a catastrophic DNA damage response. This response may be activated when nontelomeric ssDNA-binding proteins bind and protect the G overhang.In order to maintain genome integrity, the telomeric DNA from cells with linear chromosomes is packaged into a protective nucleoprotein complex (10). In the absence of this complex, the telomeres are recognized as DNA damage and subject to repair by nonhomologous end joining (33). The resulting chromosome fusions lead to genome instability (36). The protective telomeric complex is composed of a series of unique telomere proteins that bind the double-stranded region of the telomeric DNA and/or the single-strand overhang on the 3Ј G-rich strand (37). Although the exact composition of the complex varies between species, vertebrates, yeasts, plants, and ciliates all use a series of structurally related proteins to protect their telomeres. The G-overhang binding proteins all bind Gstrand DNA through a conserved OB fold motif, while the double-stranded DNA-binding proteins bind via a conserved myb motif (23,37,46).In vertebrate cells, telomeres are packaged by a core complex of six proteins which function both in telomere protection and in telomere length regulation (10). This core complex (which is sometimes called shelterin) contains two doublestranded DNA-binding proteins, TRF1 and TRF2, which anchor the complex along the length of the telomere, and the TRF1/2 interaction partners Rap1, TIN2, and TPP1. The Gstrand binding protein POT1 is also a component of the complex. Although POT1 is secured into the complex through interactions with TPP1 (17, 31, 50), POT1 molecules are also thought to bind the G-strand overhang via their OB foldcontaining DNA-binding domain (45,46). Additional telomere-associated proteins include a number of DNA damage response factors (33). However, these factors appear to bind only transiently during replication of...

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“…Figure 4 illustrates the well-known effect of 1 J/m 2 UVC on this distribution and the abrogation of the response by caffeine. 15,42 As mentioned in the Introduction, the selective inhibition of incorporation of radiolabeled DNA precursors into low molecular weight nascent DNA has been used as a reliable and reproducible indicator of the activation of the S checkpoint, which results in the inhibition of initiation of new replicons. In the present study, the abrogation of this S-checkpoint response was demonstrated by transfecting HeLa cells with RNAi to knock down specifically the expression of the checkpoint kinase Chk1.…”

Section: Resultsmentioning

confidence: 99%