Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO‐1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription

• Published in: Nucleic acids research 2004-01, Vol.32 (2), p.598-610
• Main Authors: Ling, Yan, Sankpal, Umesh T., Robertson, Andrea K., McNally, James G., Karpova, Tatiana, Robertson, Keith D.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cell Line; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - chemistry; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Silencing; Histone Deacetylases - metabolism; Humans; Kruppel-Like Transcription Factors; Mice; Protein Binding; Protein Inhibitors of Activated STAT; Protein Processing, Post-Translational; Protein Structure, Tertiary; Proteins - metabolism; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - chemistry; Repressor Proteins - metabolism; SUMO-1 protein; SUMO-1 Protein - chemistry; SUMO-1 Protein - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkh195

The de novo DNA methyltransferase Dnmt3a is one of three mammalian DNA methyltransferases that has been shown to play crucial roles in embryonic development, genomic imprinting and transcriptional silencing. Despite its importance, very little is known about how the enzymatic activity and transcriptional repression functions of Dnmt3a are regulated. Here we show that Dnmt3a interacts with multiple components of the sumoylation machinery, namely the E2 sumo conjugating enzyme Ubc9 and the E3 sumo ligases PIAS1 and PIASxα, all of which are involved in conjugating the small ubiquitin‐like modifier polypeptide, SUMO‐1, to its target proteins. Dnmt3a is modified by SUMO‐1 in vivo and in vitro and the region of Dnmt3a responsible for interaction maps to the N‐terminal regulatory domain. Functionally, sumoylation of Dnmt3a disrupts its ability to interact with histone deacetylases (HDAC1/2), but not with another interaction partner, Dnmt3b. Conditions that enhance the sumoylation of Dnmt3a in vivo abolish its capacity to repress transcription. These studies reveal a new level of regulation governing Dnmt3a whereby a post‐translational modification can dramatically regulate its interaction with specific protein partners and alter its ability to repress transcription.