CXXC

CxxC is the designation for a family of zinc-binding DNA-binding domains found in a variety of chromatin-associated proteins. The hallmark is a cysteine-rich motif often described as Cys-X-X-Cys (CxxC). In many instances the domain coordinates a zinc ion and forms a fold that recognizes DNA, with a particular affinity for unmethylated CpG dinucleotides within CpG islands.

The CxxC domain enables proteins to bind CpG-rich DNA and to recruit histone-modifying enzymes or other regulatory factors to those regions. This targeting helps shape local chromatin states and can influence transcription, DNA methylation patterns, and genome regulation. The exact effects depend on the protein and the cellular context.

Representative proteins and contexts: Notable examples include CFP1 (CXXC1), a component of the COMPASS/SET1 complex that deposits H3K4me3 at CpG islands; KDM2A and KDM2B, histone demethylases that use their CxxC domains to bind CpG-rich DNA; DNMT1, which contains a CXXC-type zinc finger in its regulatory region and can recognize unmethylated CpG; CXXC5 (IDAX), a protein involved in Wnt signaling that also contains a CxxC domain. The motif is found across diverse eukaryotes and can be present in multiple copies within a single protein.

Notes: While the core feature is the Cys-X2-Cys pair, full domain architecture and zinc coordination can vary among proteins. The study of CxxC domains contributes to understanding CpG island targeting, DNA methylation dynamics, and chromatin regulation. Related topics include CpG islands, DNA methylation, and zinc finger domains.