Zinc Coordination Is Required for and Regulates Transcription Activation by Epstein-Barr Nuclear Antigen 1

Epstein-Barr Nuclear Antigen 1 (EBNA1) is essential for Epstein-Barr virus to immortalize naïve B-cells. Upon binding a cluster of 20 cognate binding-sites termed the family of repeats, EBNA1 transactivates promoters for EBV genes that are required for immortalization. A small domain, termed UR1, that is 25 amino-acids in length, has been identified previously as essential for EBNA1 to activate transcription. In this study, we have elucidated how UR1 contributes to EBNA1's ability to transactivate. We show that zinc is necessary for EBNA1 to activate transcription, and that UR1 coordinates zinc through a pair of essential cysteines contained within it. UR1 dimerizes upon coordinating zinc, indicating that EBNA1 contains a second dimerization interface in its amino-terminus. There is a strong correlation between UR1-mediated dimerization and EBNA1's ability to transactivate cooperatively. Point mutants of EBNA1 that disrupt zinc coordination also prevent self-association, and do not activate transcription cooperatively. Further, we demonstrate that UR1 acts as a molecular sensor that regulates the ability of EBNA1 to activate transcription in response to changes in redox and oxygen partial pressure (pO2). Mild oxidative stress mimicking such environmental changes decreases EBNA1-dependent transcription in a lymphoblastoid cell-line. Coincident with a reduction in EBNA1-dependent transcription, reductions are observed in EBNA2 and LMP1 protein levels. Although these changes do not affect LCL survival, treated cells accumulate in G0/G1. These findings are discussed in the context of EBV latency in body compartments that differ strikingly in their pO2 and redox potential

Neuropsychological function is related to irritable bowel syndrome in women with premenstrual syndrome and dysmenorrhea

Background There is increasing evidence demonstrating the co-occurrence of primary dysmenorrhea (PD), premenstrual syndrome (PMS), and irritable bowel syndrome (IBS) in women. This study aimed to investigate whether women who have symptoms of IBS in addition to PD and PMS also report more severe or frequent menstruation-associated symptoms and psychological complications compared to women with PD and PMS alone. Methods The study group included 182 female University students aged 18–25 years. IBS was diagnosed using the Rome III criteria. The severity of PMS and PD was determined using a 10-point visual analog scale and PSST (Premenstrual Syndrome Screening Tool), respectively. Neuropsychological functions including cognitive function, depression score, anxiety score, stress, insomnia, daytime sleepiness, quality of life and personality were assessed using standard questionnaires. Results Of the 182 young females, 31 (17.0%) had IBS. Average days of bleeding during the menstrual cycle and mean pain severity on the PSST scale were significantly greater in the group with IBS compared to the non-IBS group (p < 0.01). The non-IBS individuals scored more favorably than the women with IBS with respect to severity of depression, insomnia, daytime sleepiness (p < 0.05). The PSST scores were significantly correlated with scores for depression (r = 0.29; p < 0.001), anxiety (r = 0.28; p < 0.001), stress (r = 0.32; p < 0.001), insomnia (r = 0.34; p < 0.001) and daytime sleepiness (r = 0.31; p < 0.001); while, they were negatively correlated with cognitive abilities (r = − 0.20; p = 0.006) and quality of life (r = − 0.42; p < 0.001). Linear regression analysis showed that the PSST scores were possibly significant factors in determining the scores for depression, anxiety, stress, quality of life, insomnia and daytime sleepiness (p < 0.05). Conclusion IBS is related to psychological comorbidities, in particular depression, sleep problems and menstrual-associated disorders. IBS may exacerbate the features of PMS which should be taken into account in the management of PMS