This entry represents a domain found in DNA methyltransferase 1-associated protein 1 (DMAP1). DNA methylation can contribute to transcriptional silencing through several transcriptionally repressive complexes, which include methyl-CpG binding domain proteins (MBDs) and histone deacetylases (HDACs). The chief enzyme that maintains mammalian DNA methylation, DNMT1, can also establish a repressive transcription complex. The non-catalytic N terminus of DNMT1 binds to HDAC2 and DMAP1, and can mediate transcriptional repression. DMAP1 has intrinsic transcription repressive activity, and binds to the transcriptional co-repressor TSG101. DMAP1 is targeted to replication foci through interaction with the far N terminus of DNMT1 throughout S phase, whereas HDAC2 joins DNMT1 and DMAP1 only during late S phase, providing a platform for how histones may become deacetylated in heterochromatin following replication [].
This domain is part of a cytosine specific DNA methyltransferase enzyme (DNMT). It functions non-catalytically to target the protein towards replication foci. This allows the DNMT1 protein to methylate the correct residues. This domain targets DMAP1 and HDAC2 to the replication foci during the S phase of mitosis. They are thought to have some importance in conversion of critical histone lysine moieties [].A structure exists for the human cytosine specific DNA methyltransferase replication foci domain [].
This entry represents DNA (cytosine-5)-methyltransferase 1 (Dnmt1; ), which methylates CpG residues, with a preference for hemimethylated DNA. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Dnmt1 mediates transcriptional repression (silencing) by establishing a repressive transcription complex where the N terminus of Dnmt1 binds to HDAC2 (histone deacetylase-2) as well as to DMAP1 (Dnmt1-associated protein) []. LSH, which is related to the SNF2 chromatin-remodelling ATPases, is also required for efficient DNA methylation [].
FKBP3, also known as FKBP25, contains the N-terminal basic tilted helix bundle (BTHB) domain and the C-terminal PPIase domain. It is a nuclear prolyl isomerase that interacts directlywith nucleic acids []. It interacts with the histone deacetylases HDAC1 and HDAC2 as well as with their transcriptional regulator Yin Yang 1 (YY1) []. It is also a microtubule-associated protein that shuttles between nucleus and cytoplasm and stabilizes the microtubule network by direct binding of the C-terminal PPIase domain []. It plays a role in the proliferation of non-small cell type lung cancer cells (NSCLC) by modulating Sp1/HDAC2/p27 [].
SUMO proteins are ubiquitin like proteins that are covalently attached to and detached from other proteins in cells to modify their function. SUMO is first activated in an ATP-dependent reaction by formation of a thioester bond with an E1 (SUMO-activating) enzyme and then transferred to the SUMO conjugating (E2) enzyme Ubc9. Ubc9 catalyses the formation of an isopeptide bond between the C-terminal of SUMO and the amino group of lysine in the target protein. Sumoylated proteins can be targeted for different cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability []. PIAS2 is an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilising the interaction between Ubc9 and the substrate, and is a SUMO-tethering factor. It plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. The effects of this transcriptional coregulation, transactivation or silencing may vary depending upon the biological context and PIAS2 isoform studied. However, it seems to be mostly involved in gene silencing. It binds to sumoylated ELK1 and enhances its transcriptional activity by preventing recruitment of HDAC2 by ELK1, thus reversing SUMO-mediated repression of ELK1 transactivation activity [, ].
