Unexpected thermodynamic signature for the interaction of hydroxymethylated DNA with MeCP2

Int J Biol Macromol. 2023 Jan 23:123373. doi: 10.1016/j.ijbiomac.2023.123373. Online ahead of print.ABSTRACTHydroxymethylated cytosine (5hmC) is a stable DNA epigenetic mark recognized by methyl-CpG binding protein 2 (MeCP2), which acts as a transcriptional regulator and a global chromatin-remodeling element. Because 5hmC triggers a gene regulation response markedly different from that produced by methylated cytosine (5mC), both modifications must affect DNA structure and/or DNA interaction with MeCP2 differently. MeCP2 is a six-domain intrinsically disordered protein (IDP) with two domains responsible for dsDNA binding: methyl-CpG binding domain (MBD) and intervening domain (ID). Here we report the detailed thermodynamic characterization of the interaction of hmCpG-DNA with MeCP2. We find that hmCpG-DNA interacts with MeCP2 in a distinctly different mode with a particular thermodynamic signature, compared to methylated or unmethylated DNA. In addition, we find evidence for Rett syndrome-associated mutations altering the interaction of MeCP2 with dsDNA in a cytosine modification-specific manner which may correlate with disease onset time and clinical severity score.PMID:36702223 | DOI:10.1016/j.ijbiomac.2023.123373
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Source Type: research