ADDz domain found in DNA (cytosine-5) methyltransferases (C5-MTases) 3b (Dnmt3b); ADDz_Dnmt3b is an active catalytic domain of Dnmt3b. Dnmt3b is a member of the Dnmt3 family and is a de novo DNA methyltransferases that has an N-terminal variable region followed by a conserved PWWP region and the cysteine-rich ADDz domain. DNA methylation is an important epigenetic mechanism involved in diverse biological processes such as embryonic development, gene expression, and genomic imprinting. The methyltransferase activity of Dnmt3a is not only responsible for the establishment of DNA methylation pattern, but is also essential for the inheritance of these patterns during mitosis. Dnmt3b is ubiquitously expressed in most adult tissues. The ADDz_Dnmt3 domain is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger. PHD zinc finger domains have been identified in more than 40 proteins that are mainly involved in chromatin mediated transcriptional control; the classical PHD zinc finger has a C4-H-C3 motif that spans about 50-80 amino acids. In ADDz, the conserved histidine residue of the PHD finger is replaced by a cysteine, and an additional zinc finger C2-C2 like motif is located about twenty residues upstream of the C4-C-C3 motif. A knockout of Dnmt3b has been shown to be lethal in the mouse model.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 436 LEDRCLSCGKKNPVSFHPLFEGGLCQSCRDRFLELFYMYDEDGYQSYCTVCCEGRELLLCSNTSCCRCFCVECLEVLVGA 515
Cdd:cd11728    1 IEDFCLSCGRSNPATFHPLFEGGLCITCKDRFLELFYMYDDDGYQSYCTVCCEGRELLLCGNASCCRCFCVDCLEVLVGP 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 172088105 516 GTAEDAKLQEPWSCYMCLPQRCHGVLRRRKDWNMRLQDFF 555
Cdd:cd11728   81 GTAAKAKEQDPWSCYMCLPQRCYGVLKRRTDWSVRLQEFF 120

ADDz domain found in DNA (cytosine-5) methyltransferases (C5-MTases) 3b (Dnmt3b); ADDz_Dnmt3b is an active catalytic domain of Dnmt3b. Dnmt3b is a member of the Dnmt3 family and is a de novo DNA methyltransferases that has an N-terminal variable region followed by a conserved PWWP region and the cysteine-rich ADDz domain. DNA methylation is an important epigenetic mechanism involved in diverse biological processes such as embryonic development, gene expression, and genomic imprinting. The methyltransferase activity of Dnmt3a is not only responsible for the establishment of DNA methylation pattern, but is also essential for the inheritance of these patterns during mitosis. Dnmt3b is ubiquitously expressed in most adult tissues. The ADDz_Dnmt3 domain is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger. PHD zinc finger domains have been identified in more than 40 proteins that are mainly involved in chromatin mediated transcriptional control; the classical PHD zinc finger has a C4-H-C3 motif that spans about 50-80 amino acids. In ADDz, the conserved histidine residue of the PHD finger is replaced by a cysteine, and an additional zinc finger C2-C2 like motif is located about twenty residues upstream of the C4-C-C3 motif. A knockout of Dnmt3b has been shown to be lethal in the mouse model.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 436 LEDRCLSCGKKNPVSFHPLFEGGLCQSCRDRFLELFYMYDEDGYQSYCTVCCEGRELLLCSNTSCCRCFCVECLEVLVGA 515
Cdd:cd11728    1 IEDFCLSCGRSNPATFHPLFEGGLCITCKDRFLELFYMYDDDGYQSYCTVCCEGRELLLCGNASCCRCFCVDCLEVLVGP 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 172088105 516 GTAEDAKLQEPWSCYMCLPQRCHGVLRRRKDWNMRLQDFF 555
Cdd:cd11728   81 GTAAKAKEQDPWSCYMCLPQRCYGVLKRRTDWSVRLQEFF 120

domain with conserved PWWP motif; conservation of Pro-Trp-Trp-Pro residues

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 172088105   230 FGIGDLVWGKIKGFSWWPAMVVSWKAT----SKRQAMPGMRWVQWFGDGKFSEISADKLVALG 288
Cdd:smart00293   1 FKPGDLVWAKMKGFPWWPALVISPKMTpdniMKRKSDENLYPVLFFGDKDTAWIPSSKLFPLT 63

DNA-cytosine methylase [Replication, recombination and repair];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 578 RRPIRVLSLFDGI---ATGylvLKELGIKVEkyIASEVcaESIAVGTVK--HEGQIKYVNDVRKITKKNIEewGPFDLVI 652
Cdd:COG0270    1 SKKLTVIDLFAGAgglSLG---FEKAGFEVV--FAVEI--DPDACETYRanFPEAKVIEGDIRDIDPEELI--PDVDLLI 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 172088105 653 GGSPCNDLSNVNPaRKGLYEGTGRLFFEFYHLLNYTRPKegdnrpfFWMFENVVAMKVNDKKDI 716
Cdd:COG0270   72 GGPPCQPFSVAGK-RKGLEDPRGTLFFEFIRIVEELRPK-------AFVLENVPGLLSSDKGKT 127

Cytosine-C5 specific DNA methylases; Methyl transfer reactions play an important role in many aspects of biology. Cytosine-specific DNA methylases are found both in prokaryotes and eukaryotes. DNA methylation, or the covalent addition of a methyl group to cytosine within the context of the CpG dinucleotide, has profound effects on the mammalian genome. These effects include transcriptional repression via inhibition of transcription factor binding or the recruitment of methyl-binding proteins and their associated chromatin remodeling factors, X chromosome inactivation, imprinting and the suppression of parasitic DNA sequences. DNA methylation is also essential for proper embryonic development and is an important player in both DNA repair and genome stability.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 581 IRVLSLFDGIATGYLVLKELGIKVekYIASEVCAESIAV-----GTVKHEGqikyvnDVRKITKKniEEWGPFDLVIGGS 655
Cdd:cd00315    1 LRVIDLFAGIGGFRLGLEKAGFEI--VAANEIDKSAAETyeanfPNKLIEG------DITKIDEK--DFIPDIDLLTGGF 70

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 172088105 656 PCNDLSNVNpARKGLYEGTGRLFFEFYHLLNYTRPKegdnrpfFWMFENVVAMKVNDK 713
Cdd:cd00315   71 PCQPFSIAG-KRKGFEDTRGTLFFEIIRILKEKKPK-------YFLLENVKGLLTHDN 120

ADDz domain found in DNA (cytosine-5) methyltransferases (C5-MTases) 3b (Dnmt3b); ADDz_Dnmt3b is an active catalytic domain of Dnmt3b. Dnmt3b is a member of the Dnmt3 family and is a de novo DNA methyltransferases that has an N-terminal variable region followed by a conserved PWWP region and the cysteine-rich ADDz domain. DNA methylation is an important epigenetic mechanism involved in diverse biological processes such as embryonic development, gene expression, and genomic imprinting. The methyltransferase activity of Dnmt3a is not only responsible for the establishment of DNA methylation pattern, but is also essential for the inheritance of these patterns during mitosis. Dnmt3b is ubiquitously expressed in most adult tissues. The ADDz_Dnmt3 domain is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger. PHD zinc finger domains have been identified in more than 40 proteins that are mainly involved in chromatin mediated transcriptional control; the classical PHD zinc finger has a C4-H-C3 motif that spans about 50-80 amino acids. In ADDz, the conserved histidine residue of the PHD finger is replaced by a cysteine, and an additional zinc finger C2-C2 like motif is located about twenty residues upstream of the C4-C-C3 motif. A knockout of Dnmt3b has been shown to be lethal in the mouse model.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 436 LEDRCLSCGKKNPVSFHPLFEGGLCQSCRDRFLELFYMYDEDGYQSYCTVCCEGRELLLCSNTSCCRCFCVECLEVLVGA 515
Cdd:cd11728    1 IEDFCLSCGRSNPATFHPLFEGGLCITCKDRFLELFYMYDDDGYQSYCTVCCEGRELLLCGNASCCRCFCVDCLEVLVGP 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 172088105 516 GTAEDAKLQEPWSCYMCLPQRCHGVLRRRKDWNMRLQDFF 555
Cdd:cd11728   81 GTAAKAKEQDPWSCYMCLPQRCYGVLKRRTDWSVRLQEFF 120

PWWP domain found in DNA (cytosine-5)-methyltransferase 3A (DNMT3A); DNMT3A, also called DNA methyltransferase HsaIIIA, DNA MTase HsaIIIA, or M.HsaIIIA, is required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. It modifies DNA in a non-processive manner and also methylates non-CpG sites. It may preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. DNMT3A is recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. It contains a PWWP domain that binds methylated histone.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 225 QDDKEFGIGDLVWGKIKGFSWWPAMVVSWKATSKRQAMPGMRWVQWFGDGKFSEISADKLVALGLFSQHFNLATFNKLVS 304
Cdd:cd20154    1 EDGRGFGIGELVWGKLRGFSWWPGRIVSWWMTGRSRAAEGTRWVMWFGDGKFSVVCVEKLMPLSSFSSAFHQATYNKQPM 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 172088105 305 YRKAMYHTLEKARVRAGKTFSSSP-------GESLEDQLKPMLEWAHGGFKPTG 351
Cdd:cd20154   81 YRKAIYEVLQVASSRAGKLFPVCPesdesdtSKAVEVQNKQMIEWALGGFQPSG 134

ADDz domain found in DNA (cytosine-5) methyltransferases (C5-MTases) 3 like (Dnmt3l); Dnmt3l is a regulator of DNA methylation, which acts by recognizing unmethylated histone H3 tails and interacting with Dnmt3a to stimulate its de novo DNA methylation activity. The ADDz_Dnmt3l domain is located in the C-terminal region of Dnmt3l that otherwise lacks some residues required for DNA methyltransferase activity. DNA methylation is an important epigenetic mechanism involved in diverse biological processes such as embryonic development, gene expression, and genomic imprinting. Dnmt3l is also associating with HDAC1 and acts as a transcriptional repressor. The ADDz_Dnmt3l domain is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger. PHD zinc finger domains have been identified in more than 40 proteins that are mainly involved in chromatin mediated transcriptional control; the classical PHD zinc finger has a C4-H-C3 motif that spans about 50-80 amino acids. In ADDz, the conserved histidine residue of the PHD finger is replaced by a cysteine, and an additional zinc finger C2-C2 like motif is located about twenty residues upstream of the C4-C-C3 motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 435 NLEDRCLSCGKKNPVSFHPLFEGGLCQSCRDRFLELFYMYDEDGYQSYCTVCCEGRELLLCSNTSCCRCFCVECLEVLVG 514
Cdd:cd11727    2 SIEEICICCGSLQIHTQHPLFHGGICAPCTEKFLEAFFLYDEDGYQAYCTICCSGETLLMCDDPDCTRCYCFECVDSLVG 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 172088105 515 AGTAEDAKLQEPWSCYMCLPQRCHGVLRRRKDWNMRLQDFF 555
Cdd:cd11727   82 PGTSEKVKATNNWVCFLCLPSSRSGLLQRKRKWRSQLKAFY 122

PWWP domain found in the DNA (cytosine-5)-methyltransferase 3 (DNMT3) family; The DNMT3 family includes DNMT3A and DNMT3B, which are required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNMT3A, also called DNA methyltransferase HsaIIIA, DNA MTase HsaIIIA, or M.HsaIIIA, modifies DNA in a non-processive manner and also methylates non-CpG sites. It may preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. DNMT3A is recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. DNMT3B, also called DNA methyltransferase HsaIIIB, DNA MTase HsaIIIB, or M.HsaIIIB, may preferentially methylate nucleosomal DNA within the nucleosome core region. DNMT3B may function as a transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Members of this family contains a PWWP domain that is responsible for establishing DNA methylation patterns during embryogenesis and gametogenesis. In tumorigenesis, DNA methylation by DNMT3B is known to play a role in the inactivation of tumor suppressor genes. In addition, a point mutation in the PWWP domain of DNMT3B has been identified in patients with ICF (immunodeficiency, centromeric instability, and facial anomalie) syndrome , a rare autosomal recessive disorder characterized by hypomethylation of classical satellite DNA.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 232 IGDLVWGKIKGFSWWPAMVVSWKATSKRQAMPGMRWVQWFGDGKFSEISADKLVALGLFSQHFNLaTFNKLVSYRKAMYH 311
Cdd:cd05835    2 IGDLVWAKLKGSPWWPGIVVSHKDCGQKPPAEGSVWVFWFGDHKVSEVPLDKILPFAEFFNKFYI-SKNSSKLYKKAVYE 80

                 ....*....
gi 172088105 312 TLEKARVRA 320
Cdd:cd05835   81 ALKEAAERS 89

domain with conserved PWWP motif; conservation of Pro-Trp-Trp-Pro residues

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 172088105   230 FGIGDLVWGKIKGFSWWPAMVVSWKAT----SKRQAMPGMRWVQWFGDGKFSEISADKLVALG 288
Cdd:smart00293   1 FKPGDLVWAKMKGFPWWPALVISPKMTpdniMKRKSDENLYPVLFFGDKDTAWIPSSKLFPLT 63

PWWP domain; The PWWP domain is named after a conserved Pro-Trp-Trp-Pro motif. The domain binds to Histone-4 methylated at lysine-20, H4K20me, suggesting that it is methyl-lysine recognition motif. Removal of two conserved aromatic residues in a hydrophobic cavity created by this domain within the full-length protein, Pdp1, abolishes the interaction o f the protein with H4K20me3. In fission yeast, Set9 is the sole enzyme that catalyzes all three states of H4K20me, and Set9-mediated H4K20me is required for efficient recruitment of checkpoint protein Crb2 to sites of DNA damage. The methylation of H4K20 is involved in a diverse array of cellular processes, such as organizing higher-order chromatin, maintaining genome stability, and regulating cell-cycle progression.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105  233 GDLVWGKIKGFSWWPAMVVSW----KATSKRQAMPGMRWVQWFGDGKFSEISADKLVALGLFSQHFNLATFNKLVS---Y 305
Cdd:pfam00855   1 GDLVWAKLKGYPWWPARVVDPeelpENVLKPKKKDGEYLVRFFGDSEFAWVKPKDLKPFDEGDEFEYLKKKKKKKKkkaF 80

                  ....
gi 172088105  306 RKAM 309
Cdd:pfam00855  81 KKAL 84

DNA-cytosine methylase [Replication, recombination and repair];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 578 RRPIRVLSLFDGI---ATGylvLKELGIKVEkyIASEVcaESIAVGTVK--HEGQIKYVNDVRKITKKNIEewGPFDLVI 652
Cdd:COG0270    1 SKKLTVIDLFAGAgglSLG---FEKAGFEVV--FAVEI--DPDACETYRanFPEAKVIEGDIRDIDPEELI--PDVDLLI 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 172088105 653 GGSPCNDLSNVNPaRKGLYEGTGRLFFEFYHLLNYTRPKegdnrpfFWMFENVVAMKVNDKKDI 716
Cdd:COG0270   72 GGPPCQPFSVAGK-RKGLEDPRGTLFFEFIRIVEELRPK-------AFVLENVPGLLSSDKGKT 127

PWWP domain found in PWWP domain-containing protein 2B (PWWP2B); PWWP2B is a paralog of PWWP2A, a H2A.Z-specific chromatin binding protein which may play an important role in the neural crest stem cell migration and differentiation during early development. PWWP2A and PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66alpha/beta, and CHD3/4. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 225 QDDKEFGIGDLVWGKIKGFSWWPAMVVSWKATSKRQAMPGMR--WVQWFGDGKFSEISADKLVAlglFSQHFNLaTFN-- 300
Cdd:cd20153    9 EEGRTVSVGDIVWGKIHGFPWWPARVLSISLSQKEDGEPSWQeaKVSWFGSPTTSLLSVSKLSP---FSEFFKL-RFNrk 84

                         90
                 ....*....|....*..
gi 172088105 301 KLVSYRKAMYHTLEKAR 317
Cdd:cd20153   85 KKGMYRKAITEAAKAAE 101

C-5 cytosine-specific DNA methylase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105  581 IRVLSLFDGIATGYLVLKELGIKVekYIASEVCAESIAVGTVKHEGQIkyVNDVRKITKKNIEEwgpFDLVIGGSPCNDL 660
Cdd:pfam00145   1 FKFIDLFAGIGGFRLGLEQAGFEC--VAANEIDKSAAKTYEANFPKVP--IGDITLIDIKDIPD---IDILTGGFPCQDF 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 172088105  661 SNVNpARKGLYEGTGRLFFEFYHLLNYTRPKegdnrpfFWMFENVVAMKVNDKK 714
Cdd:pfam00145  74 SIAG-KQKGFEDTRGTLFFEIIRIIKEKKPK-------AFLLENVKGLLSHDNG 119

PWWP domain found in glyoxylate reductase 1 (GLYR1) and similar proteins; GLYR1, also called 3-hydroxyisobutyrate dehydrogenase-like protein, cytokine-like nuclear factor N-PAC, nuclear protein NP60, or nuclear protein of 60 kDa, is a putative oxidoreductase that is recruited on chromatin and promotes KDM1B demethylase activity. It recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3). GLYR1 enhances the activity of MAP2K4 and MAP2K6 kinases to phosphorylate p38-alpha. In addition to the PWWP domain, GLYR1 also contains an AT-hook and a C-terminal NAD-binding domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 172088105 230 FGIGDLVWGKIKGFSWWPAMVVSWKATSKRQAM-PGMRWVQWFG 272
Cdd:cd05836    1 FKIGDLVWAKMKGFPPWPGKIVNPPPDLKKPPRkKKMHCVYFFG 44

PWWP domain found in PWWP domain-containing protein 2A (PWWP2A); PWWP2A is a H2A.Z-specific chromatin binding protein which may play an important role in the neural crest stem cell migration and differentiation during early development. It is also required for proper mitosis progression. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66alpha/beta, and CHD3/4. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 172088105 216 SRDGDSTEYQDDKEFGIGDLVWGKIKGFSWWPAMVVSWKATSKRQampGMR-----WVQWFGDGKFSEISadkLVALGLF 290
Cdd:cd20152    6 SKNVSKCVTPDGRTICVGDIVWAKIYGFPWWPARILAITVSRKDN---GLLvrqeaRISWFGSPTTSFLA---LSQLAPF 79

                         90       100       110
                 ....*....|....*....|....*....|..
gi 172088105 291 SQHFNlATFNKlvsYRKAMYHTLEKARVRAGK 322
Cdd:cd20152   80 LENFQ-SRFNK---KRKGLYRKAITEAAKAAK 107

PWWP domain found in Arabidopsis thaliana histone-lysine N-methyltransferase trithorax-like protein ATX3, ATX4, ATX5, and similar proteins; The family includes A. thaliana ATX3 (also called protein SET domain group 14, or trithorax-homolog protein 3), ATX4 (also called protein SET domain group 16, or trithorax-homolog protein 4) and ATX5 (also called protein SET domain group 29, or trithorax-homolog protein 5), which belong to the histone-lysine methyltransferase family. They show distinct phylogenetic origins from the family of ATX1 and ATX2. They are multi-domain containing protein that consists of an N-terminal PWWP domain, a canonical plant homeodomain (PHD) domain, a non-canonical extended PHD (ePHD) domain, and a C-terminal SET domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 172088105 233 GDLVWGKIKGFSWWPAMVV---SWKATSKRQAMPGMRWVQWFGDGK 275
Cdd:cd20143    3 GDLVWAKVGTHPFWPARVVepaEQAEEVRRRCVPGSLCVYFFGPGG 48

first PWWP domain found in nuclear receptor-binding SET domain-containing (NSD) proteins; The nuclear receptor binding SET domain (NSD) protein family consists of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 that are critical in maintaining the chromatin integrity. Reducing NSD activity through specific lysine-HMTase inhibitors appears promising in suppressing cancer growth. NSD proteins have specific mono- and dimethylase activities for H3K36, and play nonredundant roles during development. NSD1 plays a role in several pathologies, including but not limited to Sotos and Weaver syndromes, acute myeloid leukemia, breast cancer, neuroblastoma, and glioblastoma formation. NSD2 is involved in cancer cell proliferation, survival, and tumor growth, through mediating constitutive NF-kappaB signaling via the cytokine autocrine loop. NSD3 is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD proteins contain a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-proline (PWWP) domains, five plant homeodomain (PHD) fingers, and an NSD-specific Cys-His rich domain (C5HCH). This model corresponds to the first PWWP domain. This family also includes Drosophila melanogaster maternal-effect sterile 4 (dMes4) that may act as a histone-lysine N-methyltransferase required for wing morphogenesis. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 172088105 232 IGDLVWGKIKGFSWWPAMVVS---------WKATSKRQAMpgMRWVQWFGD 273
Cdd:cd20144    1 VGDLVWAKVSGHPWWPCMVTYdpesglytkIKGSGGRTYR--QYHVQFFGD 49

first PWWP domain found in nuclear SET domain-containing protein 2 (NSD2) and similar proteins; NSD2, also called histone-lysine N-methyltransferase NSD2, multiple myeloma SET domain-containing protein (MMSET), or protein trithorax-5 Wolf-Hirschhorn syndrome candidate 1 protein (WHSC1), is overexpressed frequently in the t(4;14) translocation in 15% to 20% of multiple myeloma. It plays important roles in cancer cell proliferation, survival, and tumor growth, through mediating constitutive NF-kappaB signaling via the cytokine autocrine loop. It also enhances androgen receptor (AR)-mediated transcription. The principal chromatin-regulatory activity of NSD2 is dimethylation of histone H3 at lysine 36 (H3K36me2). NSD2 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, a high mobility group (HMG) box, five PHD (plant-homeodomain) zinc finger motifs, and an NSD-specific Cys-His rich domain (C5HCH). The SET domain is responsible for histone methyltransferase activity. The PWWP, HMG, and PHD domains mediate chromatin interaction and recognition of histone marks. This model corresponds to the first PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 172088105 230 FGIGDLVWGKIKGFSWWPAMVVSWKATSKRQAMPGMR------WVQWFGD 273
Cdd:cd20162    1 YNVGDLVWSKVSGYPWWPCMVSADPLLHSHTKLKGQKksarqyHVQFFGD 50

PWWP domain found in DNA mismatch repair protein MSH6 and similar proteins; MSH6, also called G/T mismatch-binding protein (GTBP or GTMBP), MutS protein homolog 6, or MutS-alpha 160 kDa subunit (p160), is a mismatch repair protein homologous to bacterial MutS. It is a component of the post-replicative DNA mismatch repair system (MMR). It heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, it forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Mutations in MSH6 have been linked to increased cancer susceptibility, particularly in hereditary nonpolyposis colorectal cancer in humans. MSH6 contains a PWWP domain, but its role in MSH6 remains unclear. MSH6 orthologs found in Saccharomyces cerevisiae, Caenorhabditis elegans, and Arabidopsis thaliana lack the PWWP domain. PWWP domains typically recognize DNA and histone methylated lysines.

                         10        20
                 ....*....|....*....|.
gi 172088105 230 FGIGDLVWGKIKGFSWWPAMV 250
Cdd:cd05837    1 FSPGDLVWAKLEGYPWWPSLV 21

PWWP domain found in hepatoma-derived growth factor (HDGF)-related protein (HRP) family; The HRP family includes hepatoma-derived growth factor (HDGF), and HDGF-related proteins (HRPs). HDGF, also called high mobility group protein 1-like 2 (HMG-1L2), is a heparin-binding protein that acts as a transcriptional repressor with mitogenic activity for fibroblasts. It is a prognostic factor in several types of cancer. HDGFL1 is also called PWWP domain-containing protein 1 (PWWP1). Its biological function remains unclear. HDGFL2, also called HDGF-related protein 2 (HRP-2), or hepatoma-derived growth factor 2 (HDGF-2), is involved in cellular growth control, through the regulation of cyclin D1 expression. HDGFL3, also called HDGF-related protein 3 (HRP-3), enhances DNA synthesis and may play a role in cell proliferation. The family also includes PC4 and SFRS1-interacting protein (PSIP) and similar proteins. PSIP, also called CLL-associated antigen KW-7, dense fine speckles 70 kDa protein (DFS 70), lens epithelium-derived growth factor (LEDGF), or transcriptional coactivator p75/p52, acts as a transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Members of the HRP family contains a PWWP domain, which is necessary for DNA binding.

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gi 172088105 230 FGIGDLVWGKIKGFSWWPAMV 250
Cdd:cd05834    1 FKPGDLVFAKVKGYPPWPARI 21

PWWP domain found in protein BS69 and similar proteins; Protein BS69, also called zinc finger MYND domain-containing protein 11 (ZMYND11 or ZMY11), is a ubiquitously expressed nuclear protein acting as a transcriptional co-repressor in association with various transcription factors. It was originally identified as an adenovirus 5 E1A-binding protein that inhibits E1A transactivation, as well as c-Myb transcription. It also mediates repression, at least in part, through interaction with the co-repressor N-CoR. Moreover, it interacts with Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule-1 (TICAM-1, also named TRIF) to facilitate NF-kappaB activation and type I IFN induction. It associates with PIAS1, a SUMO E3 enzyme, and Ubc9, a SUMO E2 enzyme, and plays an inhibitory role in muscle and neuronal differentiation. Moreover, BS69 regulates Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)/C-terminal activation region 2 (CTAR2)-mediated NF-kappaB activation by interfering with the complex formation between TNFR-associated death domain protein (TRADD) and LMP1/CTAR2. It also cooperates with tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) in the regulation of EBV-derived LMP1/CTAR1-induced NF-kappaB activation. Furthermore, BS69 is involved in the p53-p21Cip1-mediated senescence pathway. BS69 contains a plant homeodomain (PHD) finger, a bromodomain, a proline-tryptophan-tryptophan-proline (PWWP) domain, and a MYeloid translocation protein 8, Nervy and DEAF-1 (MYND) domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

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gi 172088105 234 DLVWGKIKGFSWWPAMVVSW 253
Cdd:cd20159    8 ELVWAKQKGFPYWPAKVIQK 27