A/T Run Geometry of B-form DNA Is Independent of Bound Methyl-CpG Binding Domain, Cytosine Methylation and Flanking Sequence

Overview

Journal Sci Rep

Specialty Science

Date 2016 Aug 10

PMID 27502833

Citations 4

Authors

Jyh Yea Chia

Wen Siang Tan

Chyan Leong Ng

Nien-Jen Hu

Hooi Ling Foo

Kok Lian Ho

Affiliations

Soon will be listed here.

Abstract

DNA methylation in a CpG context can be recognised by methyl-CpG binding protein 2 (MeCP2) via its methyl-CpG binding domain (MBD). An A/T run next to a methyl-CpG maximises the binding of MeCP2 to the methylated DNA. The A/T run characteristics are reported here with an X-ray structure of MBD A140V in complex with methylated DNA. The A/T run geometry was found to be strongly stabilised by a string of conserved water molecules regardless of its flanking nucleotide sequences, DNA methylation and bound MBD. New water molecules were found to stabilise the Rett syndrome-related E137, whose carboxylate group is salt bridged to R133. A structural comparison showed no difference between the wild type and MBD A140V. However, differential scanning calorimetry showed that the melting temperature of A140V constructs in complex with methylated DNA was reduced by ~7 °C, although circular dichroism showed no changes in the secondary structure content for A140V. A band shift analysis demonstrated that the larger fragment of MeCP2 (A140V) containing the transcriptional repression domain (TRD) destabilises the DNA binding. These results suggest that the solution structure of MBD A140V may differ from the wild-type MBD although no changes in the biochemical properties of X-ray A140V were observed.

Citing Articles

Structural investigation of Rett-inducing MeCP2 mutations.

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Cytosine methylation of mitochondrial DNA at CpG sequences impacts transcription factor A DNA binding and transcription.

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Yoon J, Yoo Y, Lee J, Kim Y, Shin Y Mol Genet Genomic Med. 2018; 7(3):e532.

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Structural Basis of MeCP2 Distribution on Non-CpG Methylated and Hydroxymethylated DNA.

Sperlazza M, Bilinovich S, Sinanan L, Javier F, Williams Jr D J Mol Biol. 2017; 429(10):1581-1594.

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