Our findings indicating increased brain serotonin synthesis capacity in migraine patients are consistent with previous reports of systemic alteration of serotonin metabolism in patients without aura. Our results also suggest that the mechanism of action of beta-adrenergic antagonists for migraine prophylaxis may involve regulation of serotonin synthesis.
Several DNA damage checkpoint factors form nuclear foci in response to ionizing radiation (IR). Although the number of the initial foci decreases concomitantly with DNA double-strand break repair, some fraction of foci persists. To date, the physiological role of the persistent foci has been poorly understood. Here we examined foci of Ser1981-phosphorylated ATM in normal human diploid cells exposed to 1 Gy of X-rays. While the initial foci size was approximately 0.6 µm, the one or two of persistent focus (foci) grew, whose diameter reached 1.6 µm or more in diameter at 24 h after IR. All of the grown persistent foci of phosphorylated ATM colocalized with the persistent foci of Ser139-phosphorylated histone H2AX, MDC1, 53BP1 and NBS1, which also grew similarly. When G0-synchronized normal human cells were released immediately after 1 Gy of X-rays and incubated for 24 h, the grown large phosphorylated ATM foci (≥1.6 µm) were rarely (av. 0.9%) observed in S phase cells, while smaller foci (<1.6 µm) were frequently (av. 45.9%) found. We observed significant phosphorylation of p53 at Ser15 in cells with a single grown phosphorylated ATM focus. Furthermore, persistent inhibition of foci growth of phosphorylated ATM 4 by an ATM inhibitor, KU55933, completely abrogated p53 phosphorylation. Defective growth of the persistent IR-induced foci was observed in primary fibroblasts derived from ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) patients, which were abnormal in IR-induced G1 checkpoint.These results indicate that the growth of the persistent foci of the DNA damage checkpoint factors plays a pivotal role in G1 arrest, which amplifies G1 checkpoint signals sufficiently for phosphorylating p53 in cells with a limited number of remaining foci.5
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