In mammals, DNA methylation patterns are thought to be established during embryonic development by de novo DNA methyltransferases 3A and 3B (DNMT3A/3B) []. DNMT3A/3B work synergistically to propagate methylation patterns with DNMT3B stimulating DNMT3A activity by promoting its association with nucleosomes []. DNMT3A exists in an autoinhibitory form that can be activated by the histone H3 tail in a DNMT3L-independent manner []. DNMT3A has been linked to cancers [, , ].
DNA (cytosine-5)-methyltransferase 3-like (DNMT3L) is an enzymatically inactive regulatory factor of de novoDNA methyltransferases DNMT3A and DNMT3AB [, , ]. It is related in sequence to DNMT3A and DNMT3B, but lacks cytosine methyltransferase activity due to the absence of catalytic residues. It recognises histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2 []. It interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences []. In mouse embryonic stem cells, DNMT3L functions as a negative regulator of methylation at promoters of bivalent genes whereas favours DNA methylation at gene bodies of housekeeping genes [].
In mammals, DNA methylation patterns are thought to be established during embryonic development by de novo DNA methyltransferases 3A and 3B (DNMT3A/3B) []. DNMT3A/3B work synergistically to propagate methylation patterns with DNMT3B stimulating DNMT3A activity by promoting its association with nucleosomes []. DNMT3A exists in an autoinhibitory form that can be activated by the histone H3 tail in a DNMT3L-independent manner []. DNMT3A has been linked to cancers [, , ].This entry represents the ADDz domain found in DNA (cytosine-5)-methyltransferase 3A (DNMT3A). The ADD domain is composed of three clearly distinguishable modules that pack together through extensive hydrophobic interactions to form a single globular domain. Packed against this GATA-like finger is a second subdomain, which binds two zinc ions and closely resembles the structure reported for several PHD fingers. Finally, there is a long C-terminal α-helix that runs out from the PHD finger and makes extensive hydrophobic contacts with the N-terminal GATA finger, bringing the N- and C-termini of the ADD domain close together. This combination of fused GATA-like and PHD fingers within a single domain is thus far unique [, ].The ADD domains of the DNMT3 family have a decisive role in blocking DNMT activity in the areas of the genome with chromatin containing methylated H3K4. Furthermore, the ADD domain of DNMMT3A (ADD-3A) competes with the chromodomain (CD) of heterochromatin protein 1 alpha (HP1alpha, CDHP1alpha) for binding to the H3 tail. The DNA methyltransferase (DNMT) 3 family members DNMT3A and DNMT3B and the DNMT3-like non-enzymatic regulatory factor DNMT3L, are involved in de-novo establishment of DNA methylation patterns in early mammalian development [, ].
This is a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, AD-DATRX) found in DNMT3A proteins. The ADD domain is composed of three clearly distinguishable modules that packtogether through extensive hydrophobic interactions to form a single globulardomain. Packed against this GATA-like finger is a second subdomain,which binds two zinc ions and closely resembles the structure reported forseveral PHD fingers. Finally, there is a long C-terminal α-helix that runsout from the PHD finger and makes extensive hydrophobic contacts with the N-terminal GATA finger, bringing the N- and C-termini of the ADD domain closetogether. This combination of fused GATA-like and PHD fingers within a singledomain is thus far unique [, ].The ADD domains of the DNMT3 family have a decisive role in blocking DNMT activity in the areas of the genome with chromatin containing methylated H3K4. Furthermore, the ADD domain of DNMMT3A (ADD-3A) competes with the chromodomain (CD) of heterochromatin protein 1 alpha (HP1alpha, CDHP1alpha) for binding to the H3 tail. The DNA methyltransferase (DNMT) 3 family members DNMT3A and DNMT3B and the DNMT3-like non-enzymatic regulatory factor DNMT3L, are involved in de-novo establishment of DNA methylation patterns in early mammalian development [, ].
MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome []. p53 acts as an important defense mechanism against cancer, and is negatively regulated by interaction with the oncoprotein MDM2 []. MDM2 overexpression correlates with metastasis and advanced forms of several cancers and may be used as a cancer drug target []. In addition, MDM2 has important roles in the cell independent of p53. It interacts with several proteins such as Rb/E2F-1 complex [], the DNA methyltransferase DNMT3A [], p107 [], MTBP []and the cyclin kinase inhibitor p21 []. MDM2 also affects cell apoptosis [, ]. The core of MDM2 folds into an open bundle of four helices which is capped by two small 3-strandedβ-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain. In addition to its N-terminal p53 binding domain, MDM2 contains a central acidic domain, zinc finger domain and a C-terminal RING-finger domain.
MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome []. p53 acts as an important defense mechanism against cancer, and is negatively regulated by interaction with the oncoprotein MDM2 []. MDM2 overexpression correlates with metastasis and advanced forms of several cancers and may be used as a cancer drug target []. In addition, MDM2 has important roles in the cell independent of p53. It interacts with several proteins such as Rb/E2F-1 complex [], the DNA methyltransferase DNMT3A [], p107 [], MTBP []and the cyclin kinase inhibitor p21 []. MDM2 also affects cell apoptosis [, ].MDM2 contains an N-terminal p53-binding domain, and a C-terminal modified C2H2C4-type RING-HC finger conferring E3 ligase activity that is required for ubiquitination and nuclear export of p53. It is also responsible for the hetero-oligomerization of MDM2, which is crucial for the suppression of P53 activity during embryonic development, and the recruitment of E2 ubiquitin-conjugating enzymes []. MDM2 also harbours a RanBP2-type zinc finger (Znf-RanBP2) domain, as well as a nuclear localisation signal (NLS) and a nuclear export signal (NES), near the central acidic region. The Znf-RanBP2 domain plays an important role in mediating MDM2 binding to ribosomal proteins and thus is involved in MDM2-mediated p53 suppression.This entry represents the C-terminal modified C2H2C4-type RING-HC finger.
This entry represents the ADD domain of DNMT3B. The ADD domain is composed of three clearly distinguishable modules that packtogether through extensive hydrophobic interactions to form a single globulardomain. Packed against this GATA-like finger is a second subdomain,which binds two zinc ions and closely resembles the structure reported forseveral PHD fingers. Finally, there is a long C-terminal α-helix that runsout from the PHD finger and makes extensive hydrophobic contacts with the N-terminal GATA finger, bringing the N- and C-termini of the ADD domain closetogether. This combination of fused GATA-like and PHD fingers within a singledomain is thus far unique [, ].In mammals, DNA methylation patterns are thought to be established during embryonic development by de novo DNA methyltransferases 3A and 3B (DNMT3A/3B) []. DNMT3A/3B work synergistically to propagate methylation patterns with DNMT3B stimulating DNMT3A activity by promoting its association with nucleosomes []. Many DNMT3B isoforms from alternative splicing have been described, among which DNMT3B3 stimulates the basal activity of DNMT3 enzymes, but partially inhibits the stimulatory effect of DNMT3L, whereas DNMT3B4 significantly impairs de novo methylation [, ]. DNMT3B is involved in development and is associated with several diseases, including cancers [].
