PROSITE documentation PDOC52112

DNMT3A1 ubiquitin-dependent recruitment (UDR) domain profile

DNA methylation provides a critical epigenetic mechanism for ensuring appropriate gene silencing, imprinting and genome stability. DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. There are two main isoforms of DNMT3A: DNMT3A1 is the full-length form of the protein, while DNMT3A2 utilizes an alternative promoter and as such lacks the 223-amino-acid-long divergent N-terminal region of the full-length. Beyond the C-terminal catalytic domain (see <PDOC51555>), DNMT3A contains chromatin recognition PWWP (Pro-Trp-Trp-Pro) (see <PDOC50812>) and ADD (ATRX-DNMT3-DNMT3L) (see <PDOC51533>) domains which help to target DNMT3A to non-transcribed intergenic regions marked by di- and trimethylated histone H3 lysine 36 (H3K36me2 and H3K36me3) and unmodified histone H3 lysine 4 (H3K4me0), respectively. The N-terminal domain unique to DNMT3A1 harbors a small, folded ubiquitin-dependent recruitment (UDR) domain that interacts with nucleosomes carrying histone H2A lysine 119 mono-ubiquitylation (H2AK119ub1), a repressive histone modification deposited by polycomb repression complex 1 (PRC1). The UDR region cannot be classified as a ubiquitin binding domain in isolation or as a ubiquitin interacting motif (UIM) and can only bind within its proper nucleosomal context. The UDR interacts extensively with the nucleosome surface [1,2,3,4,5].

The DNMT3A1 UDR region interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. The N-terminal segment of DNMT3A1 UDR forms a U-turn to interact with the H2A-H2B acidic patch of the nucleosome, the central segment occupies the groove formed by H2A C-terminal segment and H3 homodimeric interface, while the C-terminal α-helix contacts both nucleosomal DNA and the ubiquitin moiety (see <PDB:8QZM>) [4,5].

The profile we developed covers the entire UDR domain.