doi:10.1016/j.ijbiomac.2023.123373engOrtega Alarcon, DavidClaveria Gimeno, RafaelVega, SoniaJorge Torres, Olga C.Esteller, ManelAbian, OlgaVelazquez Campoy, AdrianUnexpected thermodynamic signature for the interaction of hydroxymethylated DNA with MeCP2ART-2023-133170Hydroxymethylated 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.2023http://zaguan.unizar.es/record/15321710.1016/j.ijbiomac.2023.123373http://zaguan.unizar.es/record/153217oai:zaguan.unizar.es:153217info:eu-repo/grantAgreement/ES/DGA/B25-20Rinfo:eu-repo/grantAgreement/ES/DGA/E45-20Rinfo:eu-repo/grantAgreement/ES/ISCIII/CIBERehdinfo:eu-repo/grantAgreement/ES/ISCIII/CPII13-00017info:eu-repo/grantAgreement/ES/ISCIII-ERDF-ESF/PI18-00349-Investing in your futureinfo:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00info:eu-repo/grantAgreement/ES/MINECO/FEDER/BFU2016-78232-PInternational journal of biological macromolecules 232 (2023), 123373 [13 pp]by-nc-ndhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.esinfo:eu-repo/semantics/openAccess