PHD finger superfamily; The PHD finger superfamily includes a canonical plant homeodomain (PHD) finger typically characterized as Cys4HisCys3, and a non-canonical extended PHD finger, characterized as Cys2HisCys5HisCys2His. Variations include the RAG2 PHD finger characterized by Cys3His2Cys2His and the PHD finger 5 found in nuclear receptor-binding SET domain-containing proteins characterized by Cys4HisCys2His. The PHD finger is also termed LAP (leukemia-associated protein) motif or TTC (trithorax consensus) domain. Single or multiple copies of PHD fingers have been found in a variety of eukaryotic proteins involved in the control of gene transcription and chromatin dynamics. PHD fingers can recognize the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins. They also function as epigenome readers controlling gene expression through molecular recruitment of multi-protein complexes of chromatin regulators and transcription factors. The PHD finger domain SF is structurally similar to the RING and FYVE_like superfamilies.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQsADEVPEDeykcYYCDE 493
Cdd:cd15550     2 CICGFEHDDGFMICCDKCSVWQHGDCMGID-RENIPDS----YLCEQ 43

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  105 RESPPSQHNQFPLPQYTFPvmyagPRPPYSLPQPQQSQIAQPPIQILQPQKPPTQDAAVRKHSHPEQTIH-------DVT 177
Cdd:PHA03247 2605 RGDPRGPAPPSPLPPDTHA-----PDPPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRlgraaqaSSP 2679

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  178 PRQPHR-------SSISILMNTPEPNTE--------VKQQVPPQTQPQVQTNAPGLSQTEQKQPPQMQPFTHIkSKSQSP 242
Cdd:PHA03247 2680 PQRPRRraarptvGSLTSLADPPPPPPTpepaphalVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPG-GPARPA 2758

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  243 MSQVNQNTPAPTSAASRKSVSPPSKLPKQGNFKPTHERSRSTPESNATIKFRHLQVSPTGNKFARGIDLETGErnTTNAV 322
Cdd:PHA03247 2759 RPPTTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPP--TSAQP 2836

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  323 IAAAALTAAADVPLPL-----KHGDGKRNSSSASSSPILATSKATVVKLEALP--SEKKEEDQLTEPEPETEKTDDEKTE 395
Cdd:PHA03247 2837 TAPPPPPGPPPPSLPLggsvaPGGDVRRRPPSRSPAAKPAAPARPPVRRLARPavSRSTESFALPPDQPERPPQPQAPPP 2916

                         330       340       350
                  ....*....|....*....|....*....|....*..
gi 598070169  396 DETAAKLSKGSSSSPPAQQKIKDENTVSPATKFQAPP 432
Cdd:PHA03247 2917 PQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPAGAG 2953

PHD finger found in mixed lineage leukemia 5 (MLL5); MLL5 is a histone methyltransferase that plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. It contains a single plant homeodomain (PHD) finger followed by a catalytic SET domain. MLL5 can be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation by binding to the cell cycle regulator host cell factor (HCF-1), thereby facilitating the cell cycle G1 to S phase transition. It is also involved in mitotic fidelity and genomic integrity by modulating the stability of the chromosomal passenger complex (CPC) via the interaction with Borealin. Moreover, MLL5 is a component of a complex associated with retinoic acid receptor that requires GlcN Acylation of its SET domain in order to activate its histone lysine methyltransferase activity. It also participates in the camptothecin (CPT)-induced p53 activation. Furthermore, MLL5 indirectly regulates H3K4 methylation, represses cyclin A2 (CycA) expression, and promotes myogenic differentiation.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQsADEVPEDeykcYYCDE 493
Cdd:cd15550     2 CICGFEHDDGFMICCDKCSVWQHGDCMGID-RENIPDS----YLCEQ 43

PHD-finger; PHD folds into an interleaved type of Zn-finger chelating 2 Zn ions in a similar manner to that of the RING and FYVE domains. Several PHD fingers have been identified as binding modules of methylated histone H3.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 598070169   447 CICGIEDDDGFTIQCDVCYRWQHCLCMGF-QSADEVPEDEYKCYYCDES 494
Cdd:pfam00628    3 AVCGKSDDGGELVQCDGCDDWFHLACLGPpLDPAEIPSGEWLCPECKPK 51

SET domain; SET domains are protein lysine methyltransferase enzymes. SET domains appear to be protein-protein interaction domains. It has been demonstrated that SET domains mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). A subset of SET domains have been called PR domains. These domains are divergent in sequence from other SET domains, but also appear to mediate protein-protein interaction. The SET domain consists of two regions known as SET-N and SET-C. SET-C forms an unusual and conserved knot-like structure of probably functional importance. Additionally to SET-N and SET-C, an insert region (SET-I) and flanking regions of high structural variability form part of the overall structure.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169   744 IPENTPVIEYLGEIDLFKNYRNDSTNQYTSWGttKPKVLKTAIPSKDGEVSLVLDSR--FVGNESRFIRKSCpsSANCRI 821
Cdd:pfam00856   10 IPKGEFIGEYVEVLLITKEEADKRELLYYDKL--ELRLWGPYLFTLDEDSEYCIDARalYYGNWARFINHSC--DPNCEV 85

                           90       100       110
                   ....*....|....*....|....*....|..
gi 598070169   822 QPVYIPEKNtfKFMVLTSKPItlKAeshDEEL 853
Cdd:pfam00856   86 RVVYVNGGP--RIVIFALRDI--KP---GEEL 110

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  105 RESPPSQHNQFPLPQYTFPvmyagPRPPYSLPQPQQSQIAQPPIQILQPQKPPTQDAAVRKHSHPEQTIH-------DVT 177
Cdd:PHA03247 2605 RGDPRGPAPPSPLPPDTHA-----PDPPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRlgraaqaSSP 2679

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  178 PRQPHR-------SSISILMNTPEPNTE--------VKQQVPPQTQPQVQTNAPGLSQTEQKQPPQMQPFTHIkSKSQSP 242
Cdd:PHA03247 2680 PQRPRRraarptvGSLTSLADPPPPPPTpepaphalVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPG-GPARPA 2758

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  243 MSQVNQNTPAPTSAASRKSVSPPSKLPKQGNFKPTHERSRSTPESNATIKFRHLQVSPTGNKFARGIDLETGErnTTNAV 322
Cdd:PHA03247 2759 RPPTTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPP--TSAQP 2836

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  323 IAAAALTAAADVPLPL-----KHGDGKRNSSSASSSPILATSKATVVKLEALP--SEKKEEDQLTEPEPETEKTDDEKTE 395
Cdd:PHA03247 2837 TAPPPPPGPPPPSLPLggsvaPGGDVRRRPPSRSPAAKPAAPARPPVRRLARPavSRSTESFALPPDQPERPPQPQAPPP 2916

                         330       340       350
                  ....*....|....*....|....*....|....*..
gi 598070169  396 DETAAKLSKGSSSSPPAQQKIKDENTVSPATKFQAPP 432
Cdd:PHA03247 2917 PQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPAGAG 2953

DNA translocase FtsK; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 598070169   83 EPVPASAHYPQQPQQQPVRPHIRESppsQHNQFPLPQYTFPVMYAGPRPPYSlpQPQQSQIAQPPIQILQP 153
Cdd:PRK10263  783 QPVAPQPQYQQPQQPVAPQPQYQQP---QQPVAPQPQYQQPQQPVAPQPQYQ--QPQQPVAPQPQDTLLHP 848

PHD finger found in mixed lineage leukemia 5 (MLL5); MLL5 is a histone methyltransferase that plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. It contains a single plant homeodomain (PHD) finger followed by a catalytic SET domain. MLL5 can be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation by binding to the cell cycle regulator host cell factor (HCF-1), thereby facilitating the cell cycle G1 to S phase transition. It is also involved in mitotic fidelity and genomic integrity by modulating the stability of the chromosomal passenger complex (CPC) via the interaction with Borealin. Moreover, MLL5 is a component of a complex associated with retinoic acid receptor that requires GlcN Acylation of its SET domain in order to activate its histone lysine methyltransferase activity. It also participates in the camptothecin (CPT)-induced p53 activation. Furthermore, MLL5 indirectly regulates H3K4 methylation, represses cyclin A2 (CycA) expression, and promotes myogenic differentiation.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQsADEVPEDeykcYYCDE 493
Cdd:cd15550     2 CICGFEHDDGFMICCDKCSVWQHGDCMGID-RENIPDS----YLCEQ 43

PHD finger found in PHD finger protein 20 (PHF20) and PHD finger protein 20-like protein 1 (P20L1); PHF20, also termed Glioma-expressed antigen 2, or hepatocellular carcinoma-associated antigen 58, or novel zinc finger protein, or transcription factor TZP (referring to Tudor and zinc finger domain containing protein), is a regulator of NF-kappaB activation by disrupting recruitment of PP2A to p65. It also functions as a transcription factor that binds Akt and plays a role in Akt cell survival/growth signaling. Moreover, it transcriptionally regulates p53. The phosphorylation of PHF20 on Ser291 mediated by protein kinase B (PKB) is essential in tumorigenesis via the regulation of p53 mediated signaling. P20L1 is an active malignant brain tumor (MBT) domain-containing protein that binds to monomethylated lysine 142 on DNA (Cytosine-5) Methyltransferase 1 (DNMT1) (DNMT1K142me1) and colocalizes at the perinucleolar space in a SET7-dependent manner. Its MBT domain reads and controls enzyme levels of methylated DNMT1 in cells, thus representing a novel antagonist of DNMT1 proteasomal degradation. Both PHF20 and PHF20L1 contain an N-terminal MBT domain, two Tudor domains, a plant homeodomain (PHD) finger and the putative DNA-binding domains, AT hook and Cys2His2-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQSADEVPEdEYKCYYC 491
Cdd:cd15549     2 CICGVNEENGLMIQCELCLCWQHGVCMGIEEEESVPE-RYVCYVC 45

PHD finger found in PHD finger protein 20 (PHF20); PHF20, also termed Glioma-expressed antigen 2, or hepatocellular carcinoma-associated antigen 58, or novel zinc finger protein, or transcription factor TZP (referring to Tudor and zinc finger domain containing protein), is a regulator of NF-kappaB activation by disrupting recruitment of PP2A to p65. It also functions as a transcription factor that binds Akt and plays a role in Akt cell survival/growth signaling. Moreover, it transcriptionally regulates p53. The phosphorylation of PHF20 on Ser291 mediated by protein kinase B (PKB) is essential in tumorigenesis via the regulation of p53 mediated signaling. PHF20 contains an N-terminal malignant brain tumor (MBT) domain, two Tudor domains, a plant homeodomain (PHD) finger and the putative DNA-binding domains, AT hook and Cys2His2-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQSaDEVPEdEYKCYYC 491
Cdd:cd15634     2 CICEVQEENDFMIQCEECLCWQHGVCMGLLE-DNVPE-KYTCYIC 44

PHD finger found in PHD finger protein 20-like protein 1 (P20L1); P20L1 is an active malignant brain tumor (MBT) domain-containing protein that binds to monomethylated lysine 142 on DNA (Cytosine-5) Methyltransferase 1 (DNMT1) (DNMT1K142me1) and colocalizes at the perinucleolar space in a SET7-dependent manner. Its MBT domain reads and controls enzyme levels of methylated DNMT1 in cells, thus representing a novel antagonist of DNMT1 proteasomal degradation. In addition to the MBT domain, PHF20L1 also contains two Tudor domains, a plant homeodomain (PHD) finger and the putative DNA-binding domains, AT hook and Cys2His2-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQSaDEVPEdEYKCYYCDE 493
Cdd:cd15633     2 CICEMDEENGFMIQCEECLCWQHSVCMGLLE-ESIPE-QYICYICRD 46

PHD-finger; PHD folds into an interleaved type of Zn-finger chelating 2 Zn ions in a similar manner to that of the RING and FYVE domains. Several PHD fingers have been identified as binding modules of methylated histone H3.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 598070169   447 CICGIEDDDGFTIQCDVCYRWQHCLCMGF-QSADEVPEDEYKCYYCDES 494
Cdd:pfam00628    3 AVCGKSDDGGELVQCDGCDDWFHLACLGPpLDPAEIPSGEWLCPECKPK 51

PHD zinc finger; The plant homeodomain (PHD) finger is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in epigenetics and chromatin-mediated transcriptional regulation. The PHD finger binds two zinc ions using the so-called 'cross-brace' motif and is thus structurally related to the RING finger and the FYVE finger. It is not yet known if PHD fingers have a common molecular function. Several reports suggest that it can function as a protein-protein interacton domain and it was recently demonstrated that the PHD finger of p300 can cooperate with the adjacent BROMO domain in nucleosome binding in vitro. Other reports suggesting that the PHD finger is a ubiquitin ligase have been refuted as these domains were RING fingers misidentified as PHD fingers.

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|....*
gi 598070169    447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQSADEVPEDEYKCYYC 491
Cdd:smart00249    3 SVCGKPDDGGELLQCDGCDRWYHQTCLGPPLLEEEPDGKWYCPKC 47

PHD finger found in Transcription factor 19 (TCF-19), Lysine-specific demethylase KDM5A and KDM5B, and other similar proteins; TCF-19 was identified as a putative trans-activating factor with expression beginning at the late G1-S boundary in dividing cells. It functions as a novel islet factor necessary for proliferation and survival in the INS-1 beta cell line. It plays an important role in susceptibility to both Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM); it has been suggested that it may positively impact beta cell mass under conditions of beta cell stress and increased insulin demand. KDM5A was originally identified as a retinoblastoma protein (Rb)-binding partner and its inactivation may be important for Rb to promote differentiation. It is involved in transcription through interaction with TBP, p107, nuclear receptors, Myc, Sin3/HDAC, Mad1, RBP-J, CLOCK, and BMAL1. KDM5B has a restricted expression pattern in the testis, ovary, and transiently in the mammary gland of the pregnant female and has been shown to be upregulated in breast cancer, prostate cancer, and lung cancer, suggesting a potential role in tumorigenesis. Both KDM5A and KDM5B function as trimethylated histone H3 lysine 4 (H3K4me3) demethylases. This family also includes Caenorhabditis elegans Lysine-specific demethylase 7 homolog (ceKDM7A). ceKDM7A (also termed JmjC domain-containing protein 1.2, PHD finger protein 8 homolog, or PHF8 homolog) is a plant homeodomain (PHD)- and JmjC domain-containing protein that functions as a histone demethylase specific for H3K9me2 and H3K27me2. The binding of the PHD finger to H3K4me3 guides H3K9me2- and H3K27me2-specific demethylation by its catalytic JmjC domain in a trans-histone regulation mechanism. In addition, this family includes plant protein OBERON 1 and OBERON 2, Alfin1-like (AL) proteins, histone acetyltransferases (HATs) HAC, and AT-rich interactive domain-containing protein 4 (ARID4).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 598070169  448 ICGIE--DDDGFTIQCDVCYRWQHCLCMGFQSADEVPEDEYKCYYC 491
Cdd:cd15517     4 ICNLEtaAVDELWVQCDGCDKWFHQFCLGLSNERYADEDKFKCPNC 49

PHD finger 3 found in Lysine-specific demethylase 5A (KDM5A), 5B (KDM5B), and similar proteins; The family includes KDM5A and KDM5B, both of which belong to the JARID subfamily within the JmjC proteins. KDM5A, also termed Histone demethylase JARID1A, or Jumonji/ARID domain-containing protein 1A, or Retinoblastoma-binding protein 2 (RBBP-2 or RBP2), was originally identified as a retinoblastoma protein (Rb)-binding partner and its inactivation may be important for Rb to promote differentiation. It is involved in transcription through interacting with TBP, p107, nuclear receptors, Myc, Sin3/HDAC, Mad1, RBP-J, CLOCK and BMAL1. KDM5A functions as the trimethylated histone H3 lysine 4 (H3K4me3) demethylase. It also displays DNA-binding activities that can recognize the specific DNA sequence CCGCCC. KDM5B, also termed Cancer/testis antigen 31 (CT31), or Histone demethylase JARID1B, or Jumonji/ARID domain-containing protein 1B (JARID1B), or PLU-1, or retinoblastoma-binding protein 2 homolog 1 (RBP2-H1 or RBBP2H1A), has a restricted expression pattern in the testis, ovary, and transiently in the mammary gland of the pregnant female and has been shown to be upregulated in breast cancer, prostate cancer, and lung cancer, suggesting a potential role in tumorigenesis. KDM5B acts as a histone demethylase that catalyzes the removal of trimethylation of lysine 4 on histone H3 (H3K4me3), induced by polychlorinated biphenyls (PCBs). It also mediates demethylation of H3K4me2 and H3K4me1. Moreover, KDM5B functions as a negative regulator of hematopoietic stem cell (HSC) self-renewal and progenitor cell activity. KDM5B has also been shown to interact with the DNA binding transcription factors BF-1 and PAX9, as well asTIEG1/KLF10 (transforming growth factor-beta inducible early gene-1/Kruppel-like transcription factor 10), and possibly function as a transcriptional corepressor. The family also includes the Drosophila melanogaster protein little imaginal discs (Lid) that functions as a JmjC-dependent trimethyl histone H3K4 (H3K4me3) demethylase, which is required for dMyc-induced cell growth. It positively regulates Hox gene expression in S2 cells. Members in this family contain the catalytic JmjC domain, JmjN, the BRIGHT domain, which is an AT-rich interacting domain (ARID), and a Cys5HisCys2 zinc finger, as well as three plant homeodomain (PHD) fingers. This model corresponds to the third PHD finger.

                          10        20        30
                  ....*....|....*....|....*....|...
gi 598070169  459 IQCDVCYRWQHCLCMGFQSADEVPEDEYKCYYC 491
Cdd:cd15610    18 VQCDGCEEWFHLLCVGLSPEEVAEDEDYICPSC 50

PHD finger 6 found in Histone-lysine N-methyltransferase 2C (KMT2C) and PHD finger 5 found in KMT2D; KMT2C, also termed myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3), or homologous to ALR protein, is a histone H3 lysine 4 (H3K4) lysine methyltransferase that functions as a circadian factor contributing to genome-scale circadian transcription. It is a component of a large complex that acts as a coactivator of multiple transcription factors, including the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR), a critical player in BA homeostasis. The MLL3 complex is essential for p53 transactivation of small heterodimer partner (SHP). KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis. KMT2D, also termed ALL1-related protein (ALR), is encoded by the gene that was named MLL4, a fourth human homolog of Drosophila trithorax, located on chromosome 12. It enzymatically generates trimethylated histone H3 Lysine 4 (H3K4me3). It plays an essential role in differentiating the human pluripotent embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) stem cells by activating differentiation-specific genes, such as HOXA1-3 and NESTIN. KMT2D is also a part of ASCOM. Both KMT2C and KMT2D contain the catalytic domain SET, several plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, Cys2HisCys5HisCys2His, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions. This model corresponds to the sixth PHD finger of KMT2C and the fifth PHD finger of KMT2D.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 598070169  459 IQCDVCYRWQHCLCMGFQSADEVP---EDEYKCYYC 491
Cdd:cd15514    16 IQCSQCERWLHGACDSLRTEEEAEraaDNGYRCLLC 51

PHD finger found in PHF2, PHF8 and KDM7; This family includes PHF2, PHF8, KDM7, and similar proteins. PHF2, also termed GRC5, or PHD finger protein 2, is a histone lysine demethylase ubiquitously expressed in various tissues. PHF8, also termed PHD finger protein 8, or KDM7B, is a monomethylated histone H4 lysine 20(H4K20me1) demethylase that transcriptionally regulates many cell cycle genes. It also preferentially acts on H3K9me2 and H3K9me1. PHF8 is modulated by CDC20-containing anaphase-promoting complex (APC (cdc20)) and plays an important role in the G2/M transition. It acts as a critical molecular sensor for mediating retinoic acid (RA) treatment response in RAR alpha-fusion-induced leukemia. Moreover, PHF8 is essential for cytoskeleton dynamics and is associated with X-linked mental retardation. KDM7, also termed JmjC domain-containing histone demethylation protein 1D (JHDM1D), or KIAA1718, is a dual histone demethylase that catalyzes demethylation of monomethylated and dimethylated H3K9 (H3K9me2/me1) and H3K27 (H3K27me2/me1), which functions as an eraser of silencing marks on chromatin during brain development. It also plays a tumor-suppressive role by regulating angiogenesis. All family members contain a plant homeodomain (PHD) finger and a JmjC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 598070169  447 CICGIEDDDG-FTIQCDVCYRWQHCLCMGFQSADEVPEDEYKCYYC 491
Cdd:cd15554     2 CICRQPYDVTrFMIECDVCKDWFHGSCVGVEEHQANDIERYHCPNC 47

PHD finger found in ubiquitin-like PHD and RING finger domain-containing protein UHRF1 and UHRF2; UHRF1 is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma (LSCC), gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), colorectal cancer, prostate cancer, and breast cancer. UHRF1 acts as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2. Its overexpression in human lung fibroblasts results in downregulation of expression of the tumour suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of transcription factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination of TIP60. It is also an N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53 status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications. UHRF2 was originally identified as a ubiquitin ligase acting as a small ubiquitin-like modifier (SUMO) E3 ligase that enhances zinc finger protein 131 (ZNF131) SUMOylation but does not enhance ZNF131 ubiquitination. It also ubiquitinates PCNP, a PEST-containing nuclear protein. Moreover, UHRF2 functions as a nuclear protein involved in cell-cycle regulation and has been implicated in tumorigenesis. It interacts with cyclins, CDKs, p53, pRB, PCNA, HDAC1, DNMTs, G9a, methylated histone H3 lysine 9, and methylated DNA. It interacts with the cyclin E-CDK2 complex, ubiquitinates cyclins D1 and E1, induces G1 arrest, and is involved in the G1/S transition regulation. Furthermore, UHRF2 is a direct transcriptional target of the transcription factor E2F-1 in the induction of apoptosis. It recruits HDAC1 and binds to methyl-CpG. UHRF2 also participates in the maturation of Hepatitis B virus (HBV) by interacting with the HBV core protein and promoting its degradation. Both UHRF1 and UHRF2 contain an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) finger, a SET- and RING-associated (SRA) domain, and a C-terminal RING finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 598070169  447 CICGIEDDDGFTIQCDVCYRWQHCLCMGFQsADEVPEDEYkcYYC 491
Cdd:cd15525     3 HVCGGKQDPEKQLLCDECDMAYHLYCLDPP-LTSLPDDDE--WYC 44

SET domain; SET domains are protein lysine methyltransferase enzymes. SET domains appear to be protein-protein interaction domains. It has been demonstrated that SET domains mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). A subset of SET domains have been called PR domains. These domains are divergent in sequence from other SET domains, but also appear to mediate protein-protein interaction. The SET domain consists of two regions known as SET-N and SET-C. SET-C forms an unusual and conserved knot-like structure of probably functional importance. Additionally to SET-N and SET-C, an insert region (SET-I) and flanking regions of high structural variability form part of the overall structure.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169   744 IPENTPVIEYLGEIDLFKNYRNDSTNQYTSWGttKPKVLKTAIPSKDGEVSLVLDSR--FVGNESRFIRKSCpsSANCRI 821
Cdd:pfam00856   10 IPKGEFIGEYVEVLLITKEEADKRELLYYDKL--ELRLWGPYLFTLDEDSEYCIDARalYYGNWARFINHSC--DPNCEV 85

                           90       100       110
                   ....*....|....*....|....*....|..
gi 598070169   822 QPVYIPEKNtfKFMVLTSKPItlKAeshDEEL 853
Cdd:pfam00856   86 RVVYVNGGP--RIVIFALRDI--KP---GEEL 110

Topoisomerase II-associated protein PAT1; Members of this family are necessary for accurate chromosome transmission during cell division.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169    88 SAHYPQQPQQQPVRPHIRESPPSQHNQFPLPQYTFPVMYaGPRPPYSLPQPQQSQIAQPPIQILQPQKPPTQDAAVRKHS 167
Cdd:pfam09770  204 RAQAKKPAQQPAPAPAQPPAAPPAQQAQQQQQFPPQIQQ-QQQPQQQPQQPQQHPGQGHPVTILQRPQSPQPDPAQPSIQ 282

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169   168 HPEQTIHDVTPRQPHRSSiSILMNTPEPNTEVKQQVPPQTQPQVQTNAPGLSQTEQKQPPQMQPFTHiksksQSPMSQVN 247
Cdd:pfam09770  283 PQAQQFHQQPPPVPVQPT-QILQNPNRLSAARVGYPQNPQPGVQPAPAHQAHRQQGSFGRQAPIITH-----PQQLAQLS 356

                   .
gi 598070169   248 Q 248
Cdd:pfam09770  357 E 357

PHD finger found in transcription initiation factor TFIID subunit 3 (TAF3); TAF3 (also termed 140 kDa TATA box-binding protein-associated factor, TBP-associated factor 3, transcription initiation factor TFIID 140 kDa subunit (TAF140), or TAFII-140, is an integral component of TFIID) is a general initiation factor (GTF) that plays a key role in preinitiation complex (PIC) assembly through core promoter recognition. The interaction of H3K4me3 with TAF3 directs global TFIID recruitment to active genes, which regulates gene-selective functions of p53 in response to genotoxic stress. TAF3 is highly enriched in embryonic stem cells and is required for endoderm lineage differentiation and prevents premature specification of neuroectoderm and mesoderm. Moreover, TAF3, along with TRF3, forms a complex that is essential for myogenic differentiation. TAF3 contains a plant homeodomain (PHD) finger. This family also includes Drosophila melanogaster BIP2 (Bric-a-brac interacting protein 2) protein, which functions as an interacting partner of D. melanogaster p53 (Dmp53).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 598070169  448 ICGIEDDDGFTIQCDVCYRWQHCLCMGFqSADEVPEDEYKCYYC 491
Cdd:cd15522     4 ICKKPDDGSPMIGCDECDDWYHWECVGI-TDEPPEEDDWFCPKC 46

SET domain (including post-SET domain) found in ASH1-like protein (ASH1L) and similar proteins; ASH1L (EC 2.1.1.43; also termed absent small and homeotic disks protein 1 homolog, KMT2H, or lysine N-methyltransferase 2H) acts as histone-lysine N-methyltransferase that specifically methylates 'Lys-36' of histone H3 (H3K36me). It plays important roles in development; heterozygous mutation of ASH1L is associated with severe intellectual disability (ID) and multiple congenital anomaly (MCA).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169  744 IPENTPVIEYLGEI---DLFK-----NYRNDsTNQYTSwgttkpkvlktaipSKDGevSLVLDSRFVGNESRFIRKSCps 815
Cdd:cd19174    20 IKAGQFIIEYVGEVvseQEFRrrmieQYHNH-SHHYCL--------------NLDS--GMVIDGYRMGNEARFVNHSC-- 80

                  ....*..
gi 598070169  816 SANCRIQ 822
Cdd:cd19174    81 DPNCEMQ 87

PHD finger found in lysine-specific demethylase 7 (KDM7); KDM7, also termed JmjC domain-containing histone demethylation protein 1D (JHDM1D), or KIAA1718, is a dual histone demethylase that catalyzes demethylation of monomethylated and dimethylated H3K9 (H3K9me2/me1) and H3K27 (H3K27me2/me1), which functions as an eraser of silencing marks on chromatin during brain development. It also plays a tumor-suppressive role by regulating angiogenesis. KDM7 contains a plant homeodomain (PHD) that binds Lys4-trimethylated histone 3 (H3K4me3) and a jumonji domain that demethylates either H3K9me2 or H3K27me2.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 598070169  447 CICGIEDD-DGFTIQCDVCYRWQHCLCMGFQSADEVPEDEYKCYYCD 492
Cdd:cd15640     2 CVCRQPYDvNRFMIECDICKDWFHGSCVQVEEHHAADIDLYHCPNCE 48

PHD finger found in lysine-specific demethylase PHF2; PHF2, also termed GRC5, or PHD finger protein 2, is a histone lysine demethylase ubiquitously expressed in various tissues. It contains a plant homeodomain (PHD) finger and a JmjC domain and plays an important role in adipogenesis. The PHD finger domain can recognize trimethylated histone H3 lysine 4 (H3K4me3). PHF2 also has dimethylated histone H3 lysine 9(H3K9me2) demethylase activity and acts as a coactivator of several metabolism-related transcription factors. Moreover, it can demethylate ARID5B and further forms a complex with demethylated ARD5B to bind the promoter regions of target genes. The overexpression of PHF2 is involved in the progression of esophageal squamous cell carcinoma (ESCC).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 598070169  447 CICGIEDD-DGFTIQCDVCYRWQHCLCMGFQSaDEVPE-DEYKCYYCDES 494
Cdd:cd15641     2 CICRLPYDvTRFMIECDACKDWFHGSCVGVEE-EEAPDiDIYHCPNCEKT 50

SET domain (including post-SET domain) found in SET domain-containing protein 5 (SETD5) and similar proteins; SETD5 is a probable transcriptional regulator that acts via the formation of large multiprotein complexes that modify and/or remodel the chromatin. SETD5 loss-of-function mutations are a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 598070169  747 NTPVIEYLGEIDLFKNYRNDSTnqytSWGTTKPKVLktaIPSKDGEVSLVLDSRFVGNESRFIRKSCPSSANCR 820
Cdd:cd19181    30 DTLIIEYRGKVMLRQQFEVNGH----FFKRPYPFVL---FYSKFNGVEMCVDARTFGNDARFIRRSCTPNAEVR 96

PHD finger 1 found in Schizosaccharomyces pombe Lid2 complex component Lid2p and similar proteins; Lid2p is a trimethyl H3K4 (H3K4me3) demethylase responsible for H3K4 hypomethylation in heterochromatin. It interacts with the histone lysine-9 methyltransferase, Clr4, through the Dos1/Clr8-Rik1 complex, and mediates H3K9 methylation and small RNA production. It also acts cooperatively with the histone modification enzymes Set1 and Lsd1 and plays an essential role in cross-talk between H3K4 and H3K9 methylation in euchromatin. Lid2p contains a JmjC domain, three PHD fingers and a JmjN domain. This model corresponds to the first PHD finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 598070169  446 GCI-CGIEDDDGFTIQCDVCYRWQHCLCMGfQSADEVPEDEYKCYYC 491
Cdd:cd15519     1 GCEvCGLDDNEGEVLLCDGCDAEYHTSCLD-PPLGEIPPGTWFCPSC 46

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169    55 QQQQPQPQPQPVQSQQKQPQQSPMATFSEPVPASAhypqqPQQQPVRPHIRESPPSQHNQFPLPQYTFPVMYAGPRPPyS 134
Cdd:pfam03154  168 QTQPPVLQAQSGAASPPSPPPPGTTQAATAGPTPS-----APSVPPQGSPATSQPPNQTQSTAAPHTLIQQTPTLHPQ-R 241

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 598070169   135 LPQPqqsqiaQPPIQILQPQKPPTQDAAvrkHSHPEQTIHDVTPRQPH--RSSISILMN--TPEPNTEVKQQVPPQTQPQ 210
Cdd:pfam03154  242 LPSP------HPPLQPMTQPPPPSQVSP---QPLPQPSLHGQMPPMPHslQTGPSHMQHpvPPQPFPLTPQSSQSQVPPG 312

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 598070169   211 VQTNAPGLSQTEQKQPPqmqpfthikSKSQSPMSQVNQNTPAPTSAASRKSVSPPSKLP 269
Cdd:pfam03154  313 PSPAAPGQSQQRIHTPP---------SQSQLQSQQPPREQPLPPAPLSMPHIKPPPTTP 362