first BRCT domain of BRCA1-associated RING domain protein 1 (Bard1) and similar proteins; Bard1, also termed BARD-1, or RING-type E3 ubiquitin transferase BARD1, is a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. It associates with BRCA1 (breast cancer-1) to form a heterodimeric BRCA1/BARD1 complex that is responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. The BRCA1/BARD1 complex catalyzes autoubiquitination of BRCA1 and trans ubiquitination of other protein substrates. Its E3 ligase activity is dramatically reduced in the presence of UBX domain protein 1 (UBXN1). BARD-1 contains an N-terminal C3HC4-type RING-HC finger that binds BRCA1, and a C-terminal region with three ankyrin repeats and tandem BRCT domains that bind CstF-50 (cleavage stimulation factor) to modulate mRNA processing and RNAP II stability in response to DNA damage. The family corresponds to the first BRCT domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 733 LVLSCSGLTVEEKTVIAEFAELSGVTISKNWDSTVTHVIASINENGACKRTLKFMMAILEGKWILTIDWIKACMKNTKYV 812
Cdd:cd17734   1 LVLLGSGLSSEQKKLLEKLAQLLKAKVVTEFSPEVTHVVVPADERGVCPRTMKYLMGILAGKWIVSFEWVEACLKAKKLV 80

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107    14 LKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMDATCPVCKIPYHRREIRGAPHMDSLVSIYKNM--------------- 78
Cdd:TIGR00599  27 LRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPKCPLCRAEDQESKLRSNWLVSEIVESFKNLrpslleflripkttp 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107    79 ---------EDASGIKLfVSQNNPSPSDKE--------KQVRDASVEKASDKnRQGSRKGRASKRNEYGKTKEIDVDAPG 141
Cdd:TIGR00599 107 venpdlagpENSSKIEL-IEESESDGVDAEdedlqrsaTSSRALAARSTADI-LQLSSDPSKRNDADYRSEPPNEGLVQC 184

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107   142 PIVmkpsSQTKKRVQLLQNLSAESLTKPTESVETAeKPKDYTENtvirldehpslNKEGNLSPFFWLRDEDDGENSSQRT 221
Cdd:TIGR00599 185 PIC----QQRMPEKAVERHLDSECLGSPSLGASTT-FPTESNPH-----------NKSSSRFSFRTVDKSSTGETSHVDK 248

                         250       260
                  ....*....|....*....|....
gi 79480107   222 ESDQLLGTTPVNVP--SFSDLMDS 243
Cdd:TIGR00599 249 YLNSMMSKPPERLPkiNYSLLTDS 272

first BRCT domain of BRCA1-associated RING domain protein 1 (Bard1) and similar proteins; Bard1, also termed BARD-1, or RING-type E3 ubiquitin transferase BARD1, is a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. It associates with BRCA1 (breast cancer-1) to form a heterodimeric BRCA1/BARD1 complex that is responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. The BRCA1/BARD1 complex catalyzes autoubiquitination of BRCA1 and trans ubiquitination of other protein substrates. Its E3 ligase activity is dramatically reduced in the presence of UBX domain protein 1 (UBXN1). BARD-1 contains an N-terminal C3HC4-type RING-HC finger that binds BRCA1, and a C-terminal region with three ankyrin repeats and tandem BRCT domains that bind CstF-50 (cleavage stimulation factor) to modulate mRNA processing and RNAP II stability in response to DNA damage. The family corresponds to the first BRCT domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 733 LVLSCSGLTVEEKTVIAEFAELSGVTISKNWDSTVTHVIASINENGACKRTLKFMMAILEGKWILTIDWIKACMKNTKYV 812
Cdd:cd17734   1 LVLLGSGLSSEQKKLLEKLAQLLKAKVVTEFSPEVTHVVVPADERGVCPRTMKYLMGILAGKWIVSFEWVEACLKAKKLV 80

PHD-like zinc-binding domain; The members of this family are annotated as containing PHD domain, but the zinc-binding region here is not typical of PHD domains. The conformation here is a well-conserved cysteine-histidine rich region spanning 90 residues, where the Cys and His are arranged as HxxC(31)CxxC(6)CxxCxxxxCxxxxHxxC (21)CxxH.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107   602 HKNCAEWAPNVYFNDLT-----IVNLDVELTRSRRISCSCCGLK-GAALGCYNKSCKNSFHVTCAK---LIPECRWDNVK 672
Cdd:pfam13771   1 HVVCALWSPELVQRGNDsmgfpIEDIEKIPKRRWKLKCYLCKKKgGACIQCSKKNCRRAFHVTCALeagLLMQFDEDNGT 80

                  ....*.
gi 79480107   673 FVMLCP 678
Cdd:pfam13771  81 FKSYCK 86

breast cancer carboxy-terminal domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 79480107    729 FSKKLVLSCSGLTVEEKTVIAEFAELSGVTISKNWDS-TVTHVIASINENgackRTLKFMMAILEGKWILTIDWIKACM 806
Cdd:smart00292   4 FKGKTFYITGSFDKEERDELKELIEALGGKVTSSLSSkTTTHVIVGSPEG----GKLELLKAIALGIPIVKEEWLLDCL 78

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 79480107     16 CPICLSLY-NSAVSLSCNHVFCNACIVKSMKMD-ATCPVC 53
Cdd:smart00184   1 CPICLEEYlKDPVILPCGHTFCRSCIRKWLESGnNTCPIC 40

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 79480107    16 CPICLSLYN---SAVSLSCNHVFCNACIVKSMKMDATCPVCK 54
Cdd:pfam13639   3 CPICLEEFEegdKVVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

Uncharacterized conserved protein, contains RING Zn-finger [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107  14 LKCPICLSLYNSAV-SLSCNHVFCNACIVKSM-KMDATCPVCkipyHRREIRgaphMDSLVSIY----------KNMEDA 81
Cdd:COG5222 275 LKCPLCHCLLRNPMkTPCCGHTFCDECIGTALlDSDFKCPNC----SRKDVL----LDGLTPDIdkklevekalKKQRKK 346

                        90       100       110
                ....*....|....*....|....*....|...
gi 79480107  82 SGiklfVSQNNPSPSDKEKQVRDASVEKASDKN 114
Cdd:COG5222 347 VG----TSDDNNTPMSEKRKREDPNSSAVFSKA 375

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 79480107  12 RELKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMDAT--CPVCKIPYHRREI 62
Cdd:COG5574 214 ADYKCFLCLEEPEVPSCTPCGHLFCLSCLLISWTKKKYefCPLCRAKVYPKKV 266

BRCT domain, a BRCA1 C-terminus domain; This BRCT domain, a BRCA1 C-terminus region, is found on many RAP1 proteins, usually at the very N-terminus. The function in human at least of a BRCT is to contribute to the heterogeneity of the telomere DNA length, but that may not be its general function, which remains unknown.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 79480107   841 KPKLFTGLKFYImGDFELAYKGYLQDLIVAAGGTIlrrrpvSSDDNEASTIVVFSVEPSKKKT 903
Cdd:pfam16589   1 LPNLFEPLRFYI-NAIPSPSRSKLKRLIEANGGTV------VDNINPAVYIVIAPYNKTDKLA 56

first BRCT domain of BRCA1-associated RING domain protein 1 (Bard1) and similar proteins; Bard1, also termed BARD-1, or RING-type E3 ubiquitin transferase BARD1, is a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. It associates with BRCA1 (breast cancer-1) to form a heterodimeric BRCA1/BARD1 complex that is responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. The BRCA1/BARD1 complex catalyzes autoubiquitination of BRCA1 and trans ubiquitination of other protein substrates. Its E3 ligase activity is dramatically reduced in the presence of UBX domain protein 1 (UBXN1). BARD-1 contains an N-terminal C3HC4-type RING-HC finger that binds BRCA1, and a C-terminal region with three ankyrin repeats and tandem BRCT domains that bind CstF-50 (cleavage stimulation factor) to modulate mRNA processing and RNAP II stability in response to DNA damage. The family corresponds to the first BRCT domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 733 LVLSCSGLTVEEKTVIAEFAELSGVTISKNWDSTVTHVIASINENGACKRTLKFMMAILEGKWILTIDWIKACMKNTKYV 812
Cdd:cd17734   1 LVLLGSGLSSEQKKLLEKLAQLLKAKVVTEFSPEVTHVVVPADERGVCPRTMKYLMGILAGKWIVSFEWVEACLKAKKLV 80

first BRCT domain of breast cancer type 1 susceptibility protein (BRCA1) and similar proteins; BRCA1, also termed RING finger protein 53 (RNF53), is a RING finger protein encoded by BRCA1, a tumor suppressor gene that regulates all DNA double-strand break (DSB) repair pathways. BRCA1 is frequently mutated in patients with hereditary breast and ovarian cancer (HBOC). Its mutation is also associated with an increased risk of pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. It plays an important role in the DNA damage response signaling, and has been implicated in various cellular processes such as cell cycle regulation, transcriptional regulation, chromatin remodeling, DNA DSBs, and apoptosis. BRCA1 contains an N-terminal C3HC4-type RING-HC finger, and two BRCT (BRCA1 C-terminus domain) repeats at the C-terminus. The family corresponds to the first BRCT domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 738 SGLTVEEKTVIAEFAELSGVTISKNWDSTVTHVIASINENGACKRTLKFMMAILEGKWILTIDWIKACMKNTKYVSEEPY 817
Cdd:cd17735   6 SGLTPEELMLVQKFARKTGSTLTSQFTEETTHVIMKTDAELVCERTLKYFLGIAGRKWVVSYQWITQSIKEGKILPEHDF 85

                ....*.
gi 79480107 818 EITMDV 823
Cdd:cd17735  86 EVRGDV 91

Extended PHD finger found in retinoic acid-induced protein 1 (RAI1), transcription factor 20 (TCF-20) and similar proteins; The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This model includes the C-terminal ePHD/ADD (ATRX-DNMT3-DNMT3L) domain of RAI1 and TCF-20. RAI1, a homolog of stromelysin-1 PDGF (platelet-derived growth factor)-responsive element-binding protein (SPBP, also termed TCF-20), is a chromatin-binding protein implicated in the regulation of gene expression. TCF-20 is involved in transcriptional activation of the MMP3 (matrix metalloprotease 3) promoter. It also functions as a transcriptional co-regulator that enhances or represses the transcriptional activity of certain transcription factors/cofactors, such as specificity protein 1 (Sp1), E twenty-six 1 (Ets1), paired box protein 6 (Pax6), small nuclear RING-finger (SNURF)/RNF4, c-Jun, androgen receptor (AR) and estrogen receptor alpha (ERalpha). Both RAI1 and TCF-20 are strongly enriched in chromatin in interphase HeLa cells, and display low nuclear mobility, and have been implicated in Smith-Magenis syndrome and Potocki-Lupski syndrome.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 79480107 601 VHKNCAEWAPNVYFNDLTIVNLDVELTRSRRISCSCCGLKGAALGCYNKSCKNSFHVTCAKLiPECRWDNVKFVMLCPL 679
Cdd:cd15668  25 VHEDCAVWAPGVYLVGGKLYGLEEAVWVAKQSVCSSCQQTGATIGCLHKGCKAKYHYPCAVE-SGCQLDEENFSLLCPK 102

C-terminal domain of the breast cancer suppressor protein (BRCA1) and related domains; The BRCT (BRCA1 C-terminus) domain is found within many DNA damage repair and cell cycle checkpoint proteins. BRCT domains interact with each other forming homo/hetero BRCT multimers, but are also involved in BRCT-non-BRCT interactions and interactions within DNA strand breaks. BRCT tandem repeats bind to phosphopeptides; it has been shown that the repeats in human BRCA1 bind specifically to pS-X-X-F motifs, mediating the interaction between BRCA1 and the DNA helicase BACH1, or BRCA1 and CtIP, a transcriptional corepressor. It is assumed that BRCT repeats play similar roles in many signaling pathways associated with the response to DNA damage.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 79480107 733 LVLSCSGLTVEEKTVIAEFAELSGVTISKNWDSTVTHVIAsinenGACKRTLKFMMAILEGKWILTIDWIKAC 805
Cdd:cd00027   1 LVICFSGLDDEEREELKKLIEALGGKVSESLSSKVTHLIA-----KSPSGEKYYLAALAWGIPIVSPEWLLDC 68

second BRCT domain of microcephalin and similar proteins; Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. It has been implicated in chromosome condensation and DNA damage induced cellular responses. It may play a role in neurogenesis and regulation of the size of the cerebral cortex. Microcephalin contains three BRCT repeats. This family corresponds to the second repeat.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 734 VLSCSGLTVEEKTVIAEFA-ELSGVTISKNWDSTVTHVIASINengacKRTLKFMMAILEGKWILTIDWIKACMKNTKYV 812
Cdd:cd17736   2 TLVMTSVHSEEQELLESVVkKLGGFRVEDSVTEKTTHVVVGSP-----RRTLNVLLGIARGCWILSPDWVLESLEAGKWL 76

Extended PHD finger (ePHD) found in transcription factor 20 (TCF-20); The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This model corresponds to the C-terminal ePHD/ADD (ATRX-DNMT3-DNMT3L) domain of TCF-20. TCF-20, also termed nuclear factor SPBP, or protein AR1, or stromelysin-1 PDGF (platelet-derived growth factor)-responsive element-binding protein (SPRE-binding protein), is involved in transcriptional activation of the MMP3 (matrix metalloprotease 3) promoter. It is strongly enriched on chromatin in interphase HeLa cells, and displays low nuclear mobility, and has been implicated in Smith-Magenis syndrome and Potocki-Lupski syndrome. As a chromatin-binding protein, TCF-20 plays a role in the regulation of gene expression. It also functions as a transcriptional co-regulator that enhances or represses the transcriptional activity of certain transcription factors/cofactors, such as specificity protein 1 (Sp1), E twenty-six 1 (Ets1), paired box protein 6 (Pax6), small nuclear RING-finger (SNURF)/RNF4, c-Jun, androgen receptor (AR) and estrogen receptor alpha (ERalpha). TCF-20 contains an N-terminal transactivation domain, a novel DNA-binding domain with an AT-hook motif, three nuclear localization signals (NLSs) and a C-terminal ePHD/ADD domain.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 79480107 601 VHKNCAEWAPNVYFNDLTIVNLDVELTRSRRISCSCCGLKGAALGCYNKSCKNSFHVTCAkLIPECRWDNVKFVMLCP 678
Cdd:cd15699  25 VHEGCILWANGIYLVCGRLYGLQEALDIAREMKCSHCQEAGATLGCYNKGCSFRYHYPCA-IDADCLLNEENFSVRCP 101

Extended PHD finger found in histone-lysine N-methyltransferase 2A (KMT2A) and 2B (KMT2B); The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This subfamily includes the ePHD finger of histone-lysine N-methyltransferase trithorax (Trx) like proteins, KMT2A/MLL1 and KMT2B/MLL2. KMT2A and KMT2B comprise the mammalian Trx branch of COMPASS family, and are both essential for mammalian embryonic development. KMT2A regulates chromatin-mediated transcription through the catalysis of methylation of histone 3 lysine 4 (H3K4), and is frequently rearranged in acute leukemia. KMT2A functions as the catalytic subunit in the MLL1 complex. KMT2B is a second human homolog of Drosophila trithorax, located on chromosome 19 and functions as the catalytic subunit in the MLL2 complex. It plays a critical role in memory formation by mediating hippocampal H3K4 di- and trimethylation. It is also required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter. Both KMT2A and KMT2B contain a CxxC (x for any residue) zinc finger domain, three PHD fingers, this extended PHD (ePHD) finger, two FY (phenylalanine tyrosine)-rich domains, and a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 564 CAFCQCSEDTEASGEMTHYYRGEpvsADFnggskvihVHKNCAEWAPNVYFN-DLTIVNLDVELTRSRRISCSCCGLKGA 642
Cdd:cd15664   1 CALCGVYGDDEPNDAGRLLYCGQ---DEW--------VHINCALWSAEVFEEdDGSLQNVHSAVSRGRMMKCELCGKPGA 69

                        90
                ....*....|....*....
gi 79480107 643 ALGCYNKSCKNSFHVTCAK 661
Cdd:cd15664  70 TVGCCLKSCPANYHFMCAR 88

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 79480107  13 ELKCPICLSLYNSAVSLS-CNHVFCNACIVKSMKMDAT-CPVCKIPYHRRE 61
Cdd:cd16544   2 ELTCPVCQEVLKDPVELPpCRHIFCKACILLALRSSGArCPLCRGPVGKTE 52

Extended PHD finger 2 found in histone-lysine N-methyltransferase 2C (KMT2C); The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This model corresponds to the second ePHD finger of KMT2C. 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. KMT2C contains PHD fingers, two ePHD fingers, an ATPase alpha beta signature, a high mobility group (HMG)-1 box, a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) domain and two FY (phenylalanine tyrosine)-rich domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 601 VHKNCAEWAPNVYFNDL-TIVNLDVELTRSRRISCSCCGLKGAALGCYNKSCKNSFHVTCAkLIPECRWDNVKfVMLCPL 679
Cdd:cd15697  27 VHLNCALWSTEVYETQAgALINVELALRRGLQMKCVFCHKTGATSGCHRLRCTNVYHFTCA-IKAQCMFFKDK-TMLCPM 104

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 79480107  13 ELKCPICLSLYNSAVSLSCNHVFCNACIVKSMKM----DATCPVCKIPYHRR 60
Cdd:cd16597   5 ELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSqhgsEYSCPQCRATFPRR 56

BRCA1 C Terminus (BRCT) domain; The BRCT domain is found predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage. The BRCT domain of XRCC1 forms a homodimer in the crystal structure. This suggests that pairs of BRCT domains associate as homo- or heterodimers. BRCT domains are often found as tandem-repeat pairs. Structures of the BRCA1 BRCT domains revealed a basis for a widely utilized head-to-tail BRCT-BRCT oligomerization mode. This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. Disease associated missense and nonsense mutations in the BRCA1 BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107   726 FHGFSkklvLSCSGLTVEEKTVIAEFAELSGVTISKNWDSTVTHVIAsinengaCKRTLKFMMAILEGKWILTIDWIKAC 805
Cdd:pfam00533   6 FSGKT----FVITGLDGLERDELKELIEKLGGKVTDSLSKKTTHVIV-------EARTKKYLKAKELGIPIVTEEWLLDC 74

                  .
gi 79480107   806 M 806
Cdd:pfam00533  75 I 75

Extended PHD finger found in PHD finger protein 6 (PHF6) and PHD finger protein 11 (PHF11); The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This model includes the two ePHD fingers of PFH6 and the single ePHD finger of PFH11. PHF6, also termed the X-linked mental retardation disorder Borjeson-Forssman-Lehmann syndrome-associated protein, is a nucleolus, ribosomal RNA promoter-associated protein that regulates cell cycle progression by suppressing ribosomal RNA synthesis. It has been implicated in cell cycle control, genomic maintenance, and tumor suppression. PHF6 shows transcriptional repression activity through directly interacting with the nucleosome remodeling and deacetylation complex component RBBP4. PHF6 contains two non-canonical ePHD fingers. PHF11, also termed BRCA1 C-terminus-associated protein, or renal carcinoma antigen NY-REN-34, is a transcriptional co-activator of the Th1 effector cytokine genes, interleukin-2 (IL2) and interferon-gamma (IFNG), co-operating with nuclear factor kappa B (NF-kappaB). It is involved in T-cell activation and viability. Polymorphisms within PHF11 are associated with total IgE, allergic asthma and eczema.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 564 CAFCQCSEDTEASGEMThyYRGEPVSAdfnggskvihvHKNCAEWAPNVY---------FNDLTIVNLDVELTRSRRISC 634
Cdd:cd15673   1 CGFCKSGEENKETGGKL--ASGEKIAA-----------HHNCMLFSSGLVqyvspnendFGGFDIEDVKKEIKRGRKLKC 67

                        90       100
                ....*....|....*....|....*...
gi 79480107 635 SCCGLKGAALGCYNKSCKNSFHVTCAKL 662
Cdd:cd15673  68 NLCKKTGATIGCDVKQCKKTYHYHCAKK 95

Extended PHD finger found in protein Jade-1, Jade-2, Jade-3 and similar proteins; The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This model includes the ePHD finger of Jade-1 (PHF17), Jade-2 (PHF15), and Jade-3 (PHF16); each of these proteins is required for ING4 and ING5 to associate with histone acetyltransferase (HAT) HBO1 and EAF6 to form a HBO1 complex that has a histone H4-specific acetyltransferase activity, has reduced activity toward histone H3, and is responsible for the bulk of histone H4 acetylation in vivo. This family also contains Drosophila melanogaster PHD finger protein rhinoceros (RNO). It is a novel plant homeodomain (PHD)-containing nuclear protein that may function as a transcription factor that antagonizes Ras signaling by regulating transcription of key EGFR/Ras pathway regulators in the Drosophila eye. All Jade proteins contain a canonical PHD finger followed by this non-canonical ePHD finger, both of which are zinc-binding motifs.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 79480107 594 GGSKVIHVhkNCAEWAPNVYFNDLT----IVNLDvELTRSR-RISCSCCGLK-GAALGCYNKSCKNSFHVTCA------- 660
Cdd:cd15671  16 SGTKWVHV--SCALWIPEVSIGCPEkmepITKIS-HIPMSRwALVCVLCKEKtGACIQCSVKSCKTAFHVTCAfqhglem 92

                        90
                ....*....|....*...
gi 79480107 661 KLIPECRWDNVKFVMLCP 678
Cdd:cd15671  93 KTILEDEDDEVKFKSYCP 110

RING finger, HC subclass, found in tripartite motif-containing proteins, TRIM7, TRIM11 and TRIM27, and similar proteins; TRIM7, TRIM11 and TRIM27, closely related tripartite motif-containing proteins, belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM7, also known as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90), is an E3 ubiquitin-protein ligase that mediates c-Jun/AP-1 activation by Ras signalling. Its phosphorylation and activation by MSK1 in response to direct activation by the Ras-Raf-MEK-ERK pathway can stimulate TRIM7 E3 ubiquitin ligase activity in mediating Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Moreover, TRIM7 binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. TRIM11, also known as protein BIA1, or RING finger protein 92 (RNF92), is an E3 ubiquitin-protein ligase involved in the development of the central nervous system. It is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 acts as a potential therapeutic target for congenital central hypoventilation syndrome (CCHS) by mediating the degradation of CCHS-associated polyalanine-expanded Phox2b. TRIM11 modulates the function of neurogenic transcription factor Pax6 through the ubiquitin-proteosome system, and thus plays an essential role for Pax6-dependent neurogenesis. It also binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105), humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults, and further regulates ARC105 function in transforming growth factor beta (TGFbeta) signaling. Moreover, TRIM11 negatively regulates retinoic acid-inducible gene-I (RIG-I)-mediated interferon-beta (IFNbeta) production and antiviral activity by targeting TANK-binding kinase-1 (TBK1). It may contribute to the endogenous restriction of retroviruses in cells. It enhances N-tropic murine leukemia virus (N-MLV) entry by interfering with Ref1 restriction. It also suppresses the early steps of human immunodeficiency virus HIV-1 transduction, resulting in decreased reverse transcripts. TRIM27, also known as RING finger protein 76 (RNF76), RET finger protein (RFP), or zinc finger protein RFP, is a nuclear E3 ubiquitin-protein ligase that is highly expressed in testis and in various tumor cell lines. Expression of TRIM27 is associated with prognosis of colon and endometrial cancers. TRIM27 was first identified as a fusion partner of the RET receptor tyrosine kinase. It functions as a transcriptional repressor and associates with several proteins involved in transcriptional activity, such as enhancer of polycomb 1 (Epc1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex, and the cell cycle regulator retinoblastoma protein (RB1). It also interacts with HDAC1, leading to downregulation of thioredoxin binding protein 2 (TBP-2), which inhibits the function of thioredoxin. Moreover, TRIM27 mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. In addition, it inhibits muscle differentiation by modulating serum response factor (SRF) and Epc1. TRIM27 promotes a non-canonical polyubiquitination of PTEN, a lipid phosphatase that catalyzes PtdIns(3,4,5)P3 (PIP3) to PtdIns(4,5)P2 (PIP2). It is an IKKepsilon-interacting protein that regulates IkappaB kinase (IKK) function and negatively regulates signaling involved in the antiviral response and inflammation. TRIM27 also forms a protein complex with MBD4 or MBD2 or MBD3, and thus plays an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis. It is a component of an estrogen receptor 1 (ESR1) regulatory complex that is involved in estrogen receptor-mediated transcription in MCF-7 cells.

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                ....*....|....*....|....*....|....*....|....*....|....
gi 79480107  13 ELKCPICLSLYNSAVSLSCNHVFCNACIVKSMK---MDATCPVCKIPYHRREIR 63
Cdd:cd16594   5 ELTCPICLDYFTDPVTLDCGHSFCRACIARCWEepeTSASCPQCRETCPQRNLR 58

RING finger, HC subclass, found in Saccharomyces cerevisiae radiation sensitivity protein 18 (RAD18) and similar proteins; RAD18, also called RING-type E3 ubiquitin transferase RAD18, acts as a postreplication repair E3 ubiquitin-protein ligase that associates with the E2 ubiquitin conjugating enzyme UBC2/RAD6 to form the UBC2-RAD18 ubiquitin ligase complex involved in postreplicative repair (PRR) of damaged DNA. The UBC2-RAD18 complex cooperates with RAD5 and the UBC13-MMS2 dimer to attach mono-ubiquitin chains on 'Lys-164' of POL30, which is necessary for PRR. The UBC2-RAD18 complex is also involved in prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine. RAD18 is an E3 RING-finger protein belonging to the UBC2/RAD6 epistasis group. It contains a typical C3HC4-type RING-HC finger.

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gi 79480107  14 LKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMDATCPVCKIPYHRR 60
Cdd:cd23148   4 LRCHICKDLLKAPMRTPCNHTFCSFCIRTHLNNDARCPLCKAEVTES 50

RING finger, HC subclass, found in really interesting new gene proteins RING1, RING2 and similar proteins; RING1, also known as polycomb complex protein RING1, RING finger protein 1 (RNF1), or RING finger protein 1A (RING1A), is a transcriptional repressor that is associated with the Polycomb group (PcG) protein complex involved in stable repression of gene activity. RING2, also known as huntingtin-interacting protein 2-interacting protein 3, HIP2-interacting protein 3, protein DinG, RING finger protein 1B (RING1B), RING finger protein 2 (RNF2), or RING finger protein BAP-1, is an E3 ubiquitin-protein ligase that interacts with both nucleosomal DNA and an acidic patch on histone H4 to achieve the specific monoubiquitination of K119 on histone H2A (H2AK119ub), thereby playing a central role in histone code and gene regulation. Both RING1 and RING2 are core components of polycomb repressive complex 1 (PRC1) that functions as an E3-ubuiquitin ligase transferring the mono-ubuiquitin mark to the C-terminal tail of Histone H2A at K118/K119. PRC1 is also capable of chromatin compaction, a function not requiring histone tails, and this activity appears important in gene silencing. RING2 acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity. Members of this family contain a C3HC4-type RING-HC finger.

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gi 79480107  13 ELKCPICLSLYNSA-VSLSCNHVFCNACIVKSMKM-DATCPVCKIPY-HRREIRGAPHMDSLVS 73
Cdd:cd16531   1 ELMCPICLGIIKNTmTVKECLHRFCAECIEKALRLgNKECPTCRKHLpSRRSLRPDPNFDALIS 64

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

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gi 79480107     16 CPICLSLY-NSAVSLSCNHVFCNACIVKSMKMD-ATCPVC 53
Cdd:smart00184   1 CPICLEEYlKDPVILPCGHTFCRSCIRKWLESGnNTCPIC 40

RING finger, HC subclass, found in protein Deltex-3-like (DTX3L) and similar proteins; DTX3L, also known as B-lymphoma- and BAL-associated protein (BBAP) or Rhysin-2 (Rhysin2), is a RING-domain E3 ubiquitin-protein ligase that regulates endosomal sorting of the G protein-coupled receptor CXCR4 from endosomes to lysosomes. It also regulates subcellular localization of its partner protein, B aggressive lymphoma (BAL), by a dynamic nucleocytoplasmic trafficking mechanism. DTX3L has a unique N-terminus, but lacks the highly basic N-terminal motif and the central proline-rich motif present in other Deltex (DTX) family members, such as DTX1, DTX2, and DTX4. Moreover, its C-terminal region is highly homologous to DTX3. It includes a C3HC4-type RING-HC finger, and a previously unidentified C-terminal domain. DTX3L can associate with DTX1 through its unique N-terminus and further enhance self-ubiquitination.

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gi 79480107  13 ELKCPICL-SLYNSAVSLSCNHVFCNACIVKSMKMDATCPVCKIPY 57
Cdd:cd16712   3 EDECPICMdRISNKKVLPKCKHVFCAACIDKAMKYKPVCPVCGTIY 48

RING finger, HC subclass, found in Ret finger protein-like 4B (RFPL4B) and similar proteins; RFPL4B, also called RING finger protein 211 (RNF211), is an uncharacterized RING finger protein containing a typical C3HC4-type RING-HC finger.

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gi 79480107   9 RMGRELKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMD----ATCPVCK 54
Cdd:cd16623   4 RLEMEATCPICLDFFSHPISLSCAHIFCFDCIQKWMTKRedsiLTCPLCR 53

RING finger, HC subclass, found in tripartite motif-containing protein 26 (TRIM26) and similar proteins; TRIM26, also known as acid finger protein (AFP), RING finger protein 95 (RNF95), or zinc finger protein 173 (ZNF173), is an E3 ubiquitin-protein ligase that negatively regulates interferon-beta production and antiviral response through polyubiquitination and degradation of nuclear transcription factor IRF3. It functions as an important regulator for RNA virus-triggered innate immune response by bridging TBK1 to NEMO (NF-kappaB essential modulator, also known as IKKgamma) and mediating TBK1 activation. It also acts as a novel tumor suppressor of hepatocellular carcinoma by regulating cancer cell proliferation, colony forming ability, migration, and invasion. TRIM26 belongs the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

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gi 79480107  13 ELKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMDAT-----CPVCKIPYHRREIR 63
Cdd:cd16598   4 EVTCSICLDYLRDPVTIDCGHNFCRSCITDYCPISGGherpvCPLCRKPFKKENIR 59

RING finger, HC subclass, found in helicase-like transcription factor (HLTF) and similar proteins; HLTF, also known as DNA-binding protein/plasminogen activator inhibitor 1 regulator, HIP116, RING finger protein 80, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3, or sucrose nonfermenting protein 2-like 3, is a yeast RAD5 homolog found in mammals. It has both E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. It is involved in Lys-63-linked poly-ubiquitination of proliferating cell nuclear antigen (PCNA) at Lys-164 and in the regulation of DNA damage tolerance. It shows double-stranded DNA translocase activity with 3'-5' polarity, thereby facilitating regression of the replication fork. HLTF contains an N-terminal HIRAN (HIP116 and RAD5 N-terminal) domain, a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA.

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gi 79480107  16 CPICLSLYNSAVSLSCNHVFCNACIVKSMKMD-ATCPVCKIPYHRREI 62
Cdd:cd16509   6 CAICLDSLTNPVITPCAHVFCRRCICEVIQREkAKCPMCRAPLSASDL 53

Extended PHD finger found in histone-lysine N-methyltransferase 2B (KMT2B); The extended plant homeodomain (ePHD) zinc finger is characterized as Cys2HisCys5HisCys2His. This subfamily includes the ePHD finger of KMT2B. KMT2B is also called trithorax homolog 2 or WW domain-binding protein 7 (WBP-7). KMT2B is encoded by the gene that was first named myeloid/lymphoid or mixed-lineage leukemia 2 (MLL2), a second human homolog of Drosophila trithorax, located on chromosome 19. It belongs to the MLL subfamily of H3K4-specific histone lysine methyltransferases (KMT2) and is vital for normal mammalian embryonic development. KMT2B functions as the catalytic subunit in the MLL2 complex, which contains WDR5, RbBP5, ASH2L and DPY30 as integral core subunits required for the efficient methylation activity of the complex. The MLL2 complex is highly active and specific for histone 3 lysine 4 (H3K4) methylation, which stimulates chromatin transcription in a SAM- and H3K4-dependent manner. Moreover, KMT2B plays a critical role in memory formation by mediating hippocampal H3K4 di- and trimethylation. It is also required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter. KMT2B contains a CxxC (x for any residue) zinc finger domain, three PHD fingers, this ePHD finger, two FY (phenylalanine tyrosine)-rich domains, and a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) domain.

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gi 79480107 602 HKNCAEWAPNVYF-NDLTIVNLDVELTRSRRISCSCCGLKGAALGCYNKSCKNSFHVTCAKLIPECRWDNVKfvMLC 677
Cdd:cd15694  28 HVNCAIWSAEVFEeNDGSLKNVHAAVARGRQMRCEHCQKIGATVGCCLSACLSNFHFMCARASRCCFQDDKK--VFC 102

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Deltex3 (DTX3), Deltex-3-like (DTX3L) and similar proteins; This subfamily contains Deltex3 (DTX3) and Deltex-3-like (DTX3L), both of which are E3 ubiquitin-protein ligases belonging to the Deltex (DTX) family. DTX3, also known as RING finger protein 154 (RNF154), has a biological function that remains unclear. DTX3L, also known as B-lymphoma- and BAL-associated protein (BBAP) or Rhysin-2 (Rhysin2), regulates endosomal sorting of the G protein-coupled receptor CXCR4 from endosomes to lysosomes. It also regulates subcellular localization of its partner protein, B aggressive lymphoma (BAL), by a dynamic nucleocytoplasmic trafficking mechanism. In contrast to other DTXs, both DTX3 and DTX3L contain a C3HC4-type RING-HC finger, and a previously unidentified C-terminal domain. DTX3L can associate with DTX1 through its unique N termini and further enhance self-ubiquitination.

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gi 79480107  15 KCPICL-SLYNSAVSLSCNHVFCNACIVKSMKMDATCPVCKIPY 57
Cdd:cd16506   2 TCPICLdEIQNKKTLEKCKHSFCEDCIDRALQVKPVCPVCGVVY 45

RING finger, HC subclass, found in postreplication repair protein RAD18 and similar proteins; RAD18, also known as HR18 or RING finger protein 73 (RNF73), is an E3 ubiquitin-protein ligase involved in post replication repair of UV-damaged DNA via its recruitment to stalled replication forks. It associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on K164. It also interacts with another E2 ubiquitin conjugating enzyme RAD6 to form a complex that monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Moreover, Rad18 is a key factor in double-strand break DNA damage response (DDR) pathways via its association with K63-linked polyubiquitylated chromatin proteins. It can function as a mediator for DNA damage response signals to activate the G2/M checkpoint in order to maintain genome integrity and cell survival after ionizing radiation (IR) exposure. RAD18 contains a C3HC4-type RING-HC finger, a ubiquitin-binding zinc finger domain (UBZ), a SAP (SAF-A/B, Acinus and PIAS) domain, and a RAD6-binding domain (R6BD).

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gi 79480107  14 LKCPICLSLYNSAV-SLSCNHVFCNACIVKSMKMDATCPVCKIP 56
Cdd:cd16529   5 LRCPICFEYFNTAMmITQCSHNYCSLCIRRFLSYKTQCPTCRAA 48

second RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the second RING-HC finger.

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gi 79480107  13 ELKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMDATCPVCKIP 56
Cdd:cd16514   1 DLECSLCLRLLYEPVTTPCGHTFCRACLERCLDHSPKCPLCRTS 44

RING finger, HC subclass, found in Saccharomyces cerevisiae increased recombination centers protein 20 (IRC20) and similar proteins; IRC20 is an uncharacterized ATP-dependent helicase that is probably involved in a pathway contributing to genomic integrity. IRC20 contains a typical C3HC4-type RING-HC finger.

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gi 79480107  11 GRELKCPICLSLYNSAVSLSCNHVFCNACIVKSMKMDATCPVCK 54
Cdd:cd23135   1 KQKLSCSICFSEIRSGAILKCGHFFCLSCIASWLREKSTCPLCK 44

RING finger, HC subclass, found in topoisomerase I-binding arginine/serine-rich protein (Topors) and similar proteins; Topors, also known as topoisomerase I-binding RING finger protein, tumor suppressor p53- binding protein 3, or p53-binding protein 3 (p53BP3), is a ubiquitously expressed nuclear E3 ubiquitin-protein ligase that can ligate both ubiquitin and small ubiquitin-like modifier (SUMO) to substrate proteins in the nucleus. It contains an N-terminal C3HC4-type RING-HC finger which ligates ubiquitin to its target proteins including DNA topoisomerase I, p53, NKX3.1, H2AX, and the AAV-2 Rep78/68 proteins. As a RING-dependent E3 ubiquitin ligase, Topors works with the E2 enzymes UbcH5a, UbcH5c, and UbcH6, but not with UbcH7, CDC34, or UbcH2b. Topors acts as a tumor suppressor in various malignancies. It regulates p53 modification, suggesting it may be responsible for astrocyte elevated gene-1 (AEG-1, also known as metadherin, or LYRIC) ubiquitin modification. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. It also functions as a negative regulator of the prostate tumor suppressor NKX3.1. Moreover, Topors is associated with promyelocytic leukemia nuclear bodies, and may be involved in the cellular response to camptothecin. It also plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress. Furthermore, Topors is a cilia-centrosomal protein associated with autosomal dominant retinal degeneration. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa (adRP).

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gi 79480107  15 KCPICLSLYNSAVSL--SCNHVFCNACIVKSMKMDATCPVCKIPY 57
Cdd:cd16574   3 SCPICLDRFENEKAFldGCFHAFCFTCILEWSKVKNECPLCKQPF 47