Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
Nucleic Acids Res. 2024 Oct 28;52(19):11442-11454. doi: 10.1093/nar/gkae832.
Maintenance methylation, of palindromic CpG dinucleotides at DNA replication forks, is crucial for the faithful mitotic inheritance of genomic 5-methylcytosine (5mC) methylation patterns. MBD proteins use two arginine residues to recognize symmetrically-positioned methyl groups in fully-methylated 5mCpG/5mCpG and 5mCpA/TpG dinucleotides. In contrast, C2H2 zinc finger (ZF) proteins recognize CpG and CpA, whether methylated or not, within longer specific sequences in a site- and strand-specific manner. Unmethylated CpG sites, often within CpG island (CGI) promoters, need protection by protein factors to maintain their hypomethylated status. Members of the BEN domain proteins bind CGCG or CACG elements within CGIs to regulate gene expression. Despite their overall structural diversity, MBD, ZF and BEN proteins all use arginine residues to recognize guanine, adopting either a 'straight-on' or 'oblique' conformation. The straight-on conformation accommodates a methyl group in the (5mC/T)pG dinucleotide, while the oblique conformation can clash with the methyl group of 5mC, leading to preferential binding of unmethylated sequences.
维持复制叉处回文性 CpG 二核苷酸的甲基化对于基因组 5-甲基胞嘧啶（5mC）甲基化模式在有丝分裂中的忠实遗传至关重要。MBD 蛋白利用两个精氨酸残基来识别完全甲基化的 5mCpG/5mCpG 和 5mCpA/TpG 二核苷酸中对称位置的甲基基团。相比之下，C2H2 锌指（ZF）蛋白以位点和链特异性的方式识别更长特定序列中的 CpG 和 CpA，无论是否甲基化。通常位于 CpG 岛（CGI）启动子内的未甲基化 CpG 位点需要蛋白质因子的保护来维持其低甲基化状态。BEN 结构域蛋白成员结合 CGCG 或 CACG 元件在 CGIs 中以调节基因表达。尽管它们的整体结构多样性，MBD、ZF 和 BEN 蛋白都使用精氨酸残基来识别鸟嘌呤，采用“直”或“斜”构象。直构象适应（5mC/T)pG 二核苷酸中的甲基基团，而斜构象可能与 5mC 的甲基基团冲突，导致优先结合未甲基化序列。
