Structure and Hemimethylated CpG Binding of the SRA Domain from Human UHRF1

Human UHRF1((u) under bar biquitin-like P (H) under barD and (R) under bar ING (f) under bar inger (1) under bar) functions to maintain CpG DNA methylation patterns through DNA replication by co-localizing with the DNA methyltransferase DNMT1 at chromatin in mammals. Recent studies show that UHRF1 binds selectively to hemimethylated CpG via its conserved SRA ((S) under bar ET-and (R) under bar ING finger-(a) under bar ssociated) domain. However, the underlying molecular mechanism is not known. Here, we report a 1.95 angstrom resolution crystal structure of the SRA domain of human UHRF1. Using NMR structure-guided mutagenesis, electrophoretic mobility shift assay, and fluorescence anisotropy analysis, we determined key amino acid residues for methyl-DNA binding that are conserved in the SRA domain.