Abstract
Activation-induced cytidine deminase (Aid), a unique enzyme that deaminates cytosine in DNA, shuttles between the nucleus and the cytoplasm. A recent study proposed a novel function of Aid in active DNA demethylation via deamination of 5-hydroxymethylcytosine, which is converted from 5-methylcytosine by the Ten-eleven translocation (Tet) family of enzymes. In this study, we examined the effect of simultaneous expression of Aid and Tet family proteins on the subcellular localization of each protein. We found that overexpressed Aid is mainly localized in the cytoplasm, whereas Tet1 and Tet2 are localized in the nucleus, and Tet3 is localized in both the cytoplasm and the nucleus. However, nuclear Tet proteins were gradually translocated to the cytoplasm when co-expressed with Aid. We also show that Aid-mediated translocation of Tet proteins is associated with Aid shuttling. Here we propose a possible role for Aid as a regulator of the subcellular localization of Tet family proteins.
Highlights
DNA methylation is a stable epigenetic feature that is involved in gene silencing and the maintenance of long-lasting cell memories [1]
When cells were co-transfected with expression plasmids for activation-induced cytidine deaminase (Aid) and Tet1, the Tet1 localization was altered from the nucleus to the cytoplasm in the co-transfected cells, whereas Aid remained in the cytoplasm (Fig. 1)
To determine the domain responsible for the altered localization of Tet1, we performed a subcellular localization analysis using a series of deletion constructs for Tet1, as previously reported [17]; full length (FL) (1–2039 amino acids: aa) which was used in the experiment shown in Fig. 1, the catalytic domain (CD) (1367– 2039aa), and the N-terminal domain (DCD) (1–1366aa), which lacks CD (Fig. 2A)
Summary
DNA methylation is a stable epigenetic feature that is involved in gene silencing and the maintenance of long-lasting cell memories [1]. The active loss of 5-methylcytosine (5mC) independent of cell division is considered to be a major initial event in the epigenetic reprogramming of early mammalian embryos [4]. A recent study proposed a novel model for the removal of 5hmC, wherein activation-induced cytidine deaminase (Aid) induces the deamination of 5hmC, which is followed by base excision repair (BER), resulting in the conversion of 5hmC into unmethylated cytosine [9]. Based on this model for active DNA demethylation, coordinated actions of both the production and removal of 5hmC may regulate the conversion of 5mC into unmethylated cytosine. Little is known how these proteins involved in the production and removal of 5hmC affect each other
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