The autoimmune regulator (AIRE) protein is a putative transcription regulator with two plant homeodomain-type zinc fingers, a putative DNA-binding domain (SAND), and four nuclear receptor binding LXXLL motifs. We have shown here that in vitro, recombinant AIRE can form homodimers and homotetramers that were also detected in thymic protein extracts. Recombinant AIRE also oligomerizes spontaneously upon phosphorylation by cAMP dependent protein kinase A or protein kinase C. Similarly, thymic AIRE protein is phosphorylated at the tyrosine and serine/threonine residues. AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box. Competition assays revealed that sequences with one TTATTA motif and two tandem repeats of ATTGGTTA had the highest binding affinity. These findings demonstrate that AIRE is an important DNA binding molecule involved in immune regulation.Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), 1 also known as autoimmune polyglandular syndrome type 1 (APS1), is a rare autosomal recessive disorder common in isolated populations such as Finns, Sardinians, and Iranian Jews (1). This syndrome is characterized by destructive autoimmune diseases of the endocrine organs, chronic candidiasis of mucous membranes, and ectodermal disorders. APECED is caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22.3 (2-4). The AIRE gene has recently been cloned by two independent groups of investigators (5, 6). The AIRE gene consists of 14 exons coding for a 2445-base pair mRNA transcript, and the translated product is expected to have 545 amino acids with a predicted molecular mass of 57.5 kDa. The predicted AIRE protein has several domains indicative of a transcriptional regulator protein (6). AIRE harbors two zinc fingers of plant homeodomain (PHD) type. A putative DNA binding domain named SAND as well as four nuclear receptor binding LXXLL motifs, an inverted LXXLL domain, and a variant of the latter (FXXLL) hint that this protein functions as a transcription coactivator (5-7). Furthermore, a highly conserved N-terminal 100-amino acid domain in AIRE has a significant homology to the homogenously staining (HSR) domain of Sp100 and Sp140 proteins (7). This domain has been shown to function as a dimerization domain in several Sp-100 related proteins (8). At the subcellular level, AIRE can be found in the cell nucleus in a speckled pattern in domains resembling promyelocytic leukemia nuclear bodies, also known as ND10, nuclear dots, or potential oncogenic domains, associated with the AIRE homologous nuclear proteins Sp100, Sp140, and Lysp100 (9).Interestingly, it has recently been shown that AIRE can activate transcription from a reporter gene when fused to a heterologous DNA binding domain. This activation required the full-length protein or the presence of more than one activation domain. A glutathione S-transferase pull-down assay showed that AIRE formed homodimers in vitro, probably through the N-terminal domain (...

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BackgroundCytogenetic studies have demonstrated that low levels of chronic radiation exposure can potentially increase the frequency of chromosomal aberrations and aneuploidy in somatic cells. Epidemiological studies have shown that health workers occupationally exposed to ionizing radiation bear an increased risk of hematological malignancies.ObjectivesTo find the influence of occupational radiation exposure on semen characteristics, including genetic and epigenetic integrity of spermatozoa in a chronically exposed population.MethodsThis cross sectional study included 134 male volunteers of which 83 were occupationally exposed to ionizing radiation and 51 were non-exposed control subjects. Semen characteristics, sperm DNA fragmentation, aneuploidy and incidence of global hypermethylation in the spermatozoa were determined and compared between the non-exposed and the exposed group.ResultsDirect comparison of the semen characteristics between the non-exposed and the exposed population revealed significant differences in motility characteristics, viability, and morphological abnormalities (P<0.05–0.0001). Although, the level of sperm DNA fragmentation was significantly higher in the exposed group as compared to the non-exposed group (P<0.05–0.0001), the incidence of sperm aneuploidy was not statistically different between the two groups. However, a significant number of hypermethylated spermatozoa were observed in the exposed group in comparison to non-exposed group (P<0.05).ConclusionsWe provide the first evidence on the detrimental effects of occupational radiation exposure on functional, genetic and epigenetic integrity of sperm in health workers. However, further studies are required to confirm the potential detrimental effects of ionizing radiation in these subjects.

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