Academician Andrew H.-J. Wang and his team at the Institute of Biological Chemistry have recently found that the C-terminal D/E-rich domain of MBD3 was able to associate with the Z-DNA binding domain (Zα) of ADAR1. The D/E-rich domain of MBD3 may act as a DNA mimic to compete with Z-DNA for binding to Zα. The interplay of MBD3 and ADAR1 may participate in regulating the local DNA conformational transition between B-DNA and Z-DNA and thereby results in alterations in gene expression.

The most abundant DNA conformation in cells is B-DNA, a canonical right-handed double helix. In addition, a left-handed Z-DNA occurs transiently during transcription. In 1979, Wang et al. first solved the crystal structure of Z-DNA, named for the zig-zag sugar phosphate backbone. The Z-DNA formation favors alternating purine/pyrimidine residues, such as CpG repeats. The formation of Z-DNA in vivo requires energy that is provided by negative DNA supercoiling driven by a moving RNA polymerase or chromatin remodeling activity. In addition, Zα can induce and stabilize the Z-DNA conformation. The biological roles of Z-DNA/Z-DNA binding protein have not been fully defined. Accumulating studies have demonstrated that the Z-DNA formation in promoter regions is correlated with transcriptional activity.

Zα interacted with the C-terminal acidic region of MBD3, a D/E-rich domain, with high affinity. Dimerization of MBD3 via intermolecular interaction of the D/E-rich domain and its N-terminal DNA binding domain, a methyl-CpG-binding domain (MBD), attenuated the high affinity interaction of Zα and the D/E-rich domain. Accordingly, MBD3 in cells may bind to the nearby regions close to the Z-DNA-forming sites via the MBD domain and thereby releases the D/E-rich domain, which is able to substitute Z-DNA for Zα binding. The Zα-free Z-DNA becomes relatively unstable and then relaxes back to B-DNA. This study represents a novel model of regulatory mechanism for local DNA conformational transition. Since both MBD3 and ADAR1 are involved in embryonic stem cell pluripotency and differentiation, it is interesting to study in the future the relationship between Z-DNA and embryonic development.

The full research article entitled “The C-terminal D/E-rich domain of MBD3 is a putative Z-DNA mimic that competes for Zα DNA-binding activity” was published in Nucleic Acids Research on October 10, 2018. The first author of the publication is Chi-Hua Lee, a postdoctoral fellow in Dr. Wang’s lab.

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