UHRF1_RAT
ID UHRF1_RAT Reviewed; 774 AA.
AC Q7TPK1; Q4FZR4;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2005, sequence version 2.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=E3 ubiquitin-protein ligase UHRF1;
DE EC=2.3.2.27;
DE AltName: Full=Liver regeneration-related protein LRRG126;
DE AltName: Full=RING-type E3 ubiquitin transferase UHRF1;
DE AltName: Full=Ubiquitin-like PHD and RING finger domain-containing protein 1;
DE AltName: Full=Ubiquitin-like-containing PHD and RING finger domains protein 1;
GN Name=Uhrf1; ORFNames=Ac2-121;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RA Xu C.S., Li W.Q., Li Y.C., Wang G.P., Chai L.Q., Yuan J.Y., Yang K.J.,
RA Yan H.M., Chang C.F., Zhao L.F., Ma H., Wang L., Wang S.F., Han H.P.,
RA Shi J.B., Rahman S., Wang Q.N., Zhang J.B.;
RT "Liver regeneration after PH.";
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 381-774.
RC TISSUE=Thymus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-91; SER-93; SER-95; SER-284
RP AND SER-751, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Multidomain protein that acts as a key epigenetic regulator
CC by bridging DNA methylation and chromatin modification. Specifically
CC recognizes and binds hemimethylated DNA at replication forks via its
CC YDG domain and recruits DNMT1 methyltransferase to ensure faithful
CC propagation of the DNA methylation patterns through DNA replication. In
CC addition to its role in maintenance of DNA methylation, also plays a
CC key role in chromatin modification: through its tudor-like regions and
CC PHD-type zinc fingers, specifically recognizes and binds histone H3
CC trimethylated at 'Lys-9' (H3K9me3) and unmethylated at 'Arg-2'
CC (H3R2me0), respectively, and recruits chromatin proteins. Enriched in
CC pericentric heterochromatin where it recruits different chromatin
CC modifiers required for this chromatin replication. Also localizes to
CC euchromatic regions where it negatively regulates transcription
CC possibly by impacting DNA methylation and histone modifications. Has E3
CC ubiquitin-protein ligase activity by mediating the ubiquitination of
CC target proteins such as histone H3 and PML. It is still unclear how E3
CC ubiquitin-protein ligase activity is related to its role in chromatin
CC in vivo. Plays a role in DNA repair by cooperating with UHRF1 to ensure
CC recruitment of FANCD2 to interstrand crosslinks (ICLs) leading to
CC FANCD2 activation (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with DNMT3A and DNMT3B. Interacts with DNMT1; the
CC interaction is direct. Interacts with USP7; leading to its
CC deubiquitination. Interacts with histone H3. Interacts with HDAC1, but
CC not with HDAC2. Interacts with UHRF1BP1. Interacts with PML. Interacts
CC with EHMT2. Binds methylated CpG containing oligonucleotides (By
CC similarity). Interacts with ZNF263; recruited to the SIX3 promoter
CC along with other proteins involved in chromatin modification and
CC transcriptional corepression where it contributes to transcriptional
CC repression (By similarity). Interacts with UHRF2 (By similarity).
CC Interacts with FANCD2 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:Q96T88}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00358}.
CC Note=Localizes to replication foci. Enriched in pericentric
CC heterochromatin. Also localizes to euchromatic regions (By similarity).
CC {ECO:0000250}.
CC -!- DOMAIN: The tudor-like regions specifically recognize and bind histone
CC H3 unmethylated at 'Arg-2' (H3R2me0), while the PHD-type zinc finger
CC specifically recognizes and binds histone H3 trimethylated at 'Lys-9'
CC (H3K9me3). The tudor-like regions simultaneously recognizes H3K9me3
CC through a conserved aromatic cage in the first tudor-like subdomain and
CC unmodified H3K4 (H3K4me0) within a groove between the tandem
CC subdomains. The linker region plays a role in the formation of a
CC histone H3-binding hole between the reader modules formed by the tudor-
CC like regions and the PHD-type zinc finger by making extended contacts
CC with the tandem tudor-like regions (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The YDG domain (also named SRA domain) specifically recognizes
CC and binds hemimethylated DNA at replication forks (DNA that is only
CC methylated on the mother strand of replicating DNA). It contains a
CC binding pocket that accommodates the 5-methylcytosine that is flipped
CC out of the duplex DNA. 2 specialized loops reach through the resulting
CC gap in the DNA from both the major and the minor grooves to read the
CC other 3 bases of the CpG duplex. The major groove loop confers both
CC specificity for the CpG dinucleotide and discrimination against
CC methylation of deoxycytidine of the complementary strand. The YDG
CC domain also recognizes and binds 5-hydroxymethylcytosine (5hmC) (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: The RING finger is required for ubiquitin ligase activity.
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation at Ser-295 of the linker region decreases the
CC binding to H3K9me3. Phosphorylation at Ser-631 by CDK1 during M phase
CC impairs interaction with USP7, preventing deubiquitination and leading
CC to degradation by the proteasome (By similarity). {ECO:0000250}.
CC -!- PTM: Ubiquitinated; which leads to proteasomal degradation.
CC Autoubiquitinated; interaction with USP7 leads to deubiquitination and
CC prevents degradation. Ubiquitination and degradation takes place during
CC M phase, when phosphorylation at Ser-631 prevents interaction with USP7
CC and subsequent deubiquitination. Polyubiquitination may be stimulated
CC by DNA damage (By similarity). {ECO:0000250}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAP86266.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AY321334; AAP86266.1; ALT_INIT; mRNA.
DR EMBL; BC099224; AAH99224.1; -; mRNA.
DR RefSeq; NP_001008882.1; NM_001008882.1.
DR AlphaFoldDB; Q7TPK1; -.
DR SMR; Q7TPK1; -.
DR STRING; 10116.ENSRNOP00000066794; -.
DR iPTMnet; Q7TPK1; -.
DR PhosphoSitePlus; Q7TPK1; -.
DR jPOST; Q7TPK1; -.
DR PaxDb; Q7TPK1; -.
DR PRIDE; Q7TPK1; -.
DR GeneID; 316129; -.
DR KEGG; rno:316129; -.
DR CTD; 29128; -.
DR RGD; 1595855; Uhrf1.
DR eggNOG; ENOG502QRDQ; Eukaryota.
DR InParanoid; Q7TPK1; -.
DR OrthoDB; 705927at2759; -.
DR PhylomeDB; Q7TPK1; -.
DR UniPathway; UPA00143; -.
DR PRO; PR:Q7TPK1; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:RGD.
DR GO; GO:0000791; C:euchromatin; ISS:UniProtKB.
DR GO; GO:0000792; C:heterochromatin; ISS:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; ISO:RGD.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0005657; C:replication fork; ISS:UniProtKB.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0044729; F:hemi-methylated DNA-binding; ISS:UniProtKB.
DR GO; GO:0042393; F:histone binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0008327; F:methyl-CpG binding; ISO:RGD.
DR GO; GO:0035064; F:methylated histone binding; ISS:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:RGD.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0010390; P:histone monoubiquitination; ISO:RGD.
DR GO; GO:0016574; P:histone ubiquitination; ISS:UniProtKB.
DR GO; GO:0010216; P:maintenance of DNA methylation; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:0050678; P:regulation of epithelial cell proliferation; ISO:RGD.
DR GO; GO:0043434; P:response to peptide hormone; IEP:RGD.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR Gene3D; 2.30.280.10; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR015947; PUA-like_sf.
DR InterPro; IPR036987; SRA-YDG_sf.
DR InterPro; IPR003105; SRA_YDG.
DR InterPro; IPR021991; TTD_dom.
DR InterPro; IPR000626; Ubiquitin-like_dom.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR InterPro; IPR045134; UHRF1/2-like.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR001965; Znf_PHD.
DR InterPro; IPR019787; Znf_PHD-finger.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR14140; PTHR14140; 1.
DR Pfam; PF00628; PHD; 1.
DR Pfam; PF02182; SAD_SRA; 1.
DR Pfam; PF12148; TTD; 1.
DR Pfam; PF00240; ubiquitin; 1.
DR SMART; SM00249; PHD; 1.
DR SMART; SM00184; RING; 2.
DR SMART; SM00466; SRA; 1.
DR SMART; SM00213; UBQ; 1.
DR SUPFAM; SSF54236; SSF54236; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
DR SUPFAM; SSF88697; SSF88697; 1.
DR PROSITE; PS50053; UBIQUITIN_2; 1.
DR PROSITE; PS51015; YDG; 1.
DR PROSITE; PS01359; ZF_PHD_1; 1.
DR PROSITE; PS50016; ZF_PHD_2; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell cycle; Chromatin regulator; DNA damage; DNA repair;
KW DNA-binding; Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Repeat; Repressor; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..774
FT /note="E3 ubiquitin-protein ligase UHRF1"
FT /id="PRO_0000056146"
FT DOMAIN 1..78
FT /note="Ubiquitin-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT DOMAIN 416..578
FT /note="YDG"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00358"
FT ZN_FING 296..363
FT /note="PHD-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00146"
FT ZN_FING 705..744
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 83..120
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 129..205
FT /note="Tudor-like 1"
FT REGION 212..280
FT /note="Tudor-like 2"
FT REGION 293..298
FT /note="Linker"
FT /evidence="ECO:0000250"
FT REGION 330..334
FT /note="Histone H3R2me0 binding"
FT /evidence="ECO:0000250"
FT REGION 350..352
FT /note="Histone H3R2me0 binding"
FT /evidence="ECO:0000250"
FT REGION 382..605
FT /note="Methyl-CpG binding and interaction with HDAC1"
FT /evidence="ECO:0000250"
FT REGION 442..443
FT /note="Required to promote base flipping"
FT /evidence="ECO:0000250"
FT REGION 463..466
FT /note="Required for formation of a 5-methylcytosine-binding
FT pocket"
FT /evidence="ECO:0000250"
FT REGION 475..478
FT /note="Required for formation of a 5-methylcytosine-binding
FT pocket"
FT /evidence="ECO:0000250"
FT REGION 616..657
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 105..120
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 630..657
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 460..461
FT /ligand="DNA"
FT /ligand_id="ChEBI:CHEBI:16991"
FT /ligand_part="5-methylcytosine group"
FT /ligand_part_id="ChEBI:CHEBI:65274"
FT /evidence="ECO:0000250"
FT BINDING 466
FT /ligand="DNA"
FT /ligand_id="ChEBI:CHEBI:16991"
FT /ligand_part="5-methylcytosine group"
FT /ligand_part_id="ChEBI:CHEBI:65274"
FT /evidence="ECO:0000250"
FT SITE 313
FT /note="Histone H3K4me0 binding"
FT /evidence="ECO:0000250"
FT SITE 324
FT /note="Histone H3R2me0 binding"
FT /evidence="ECO:0000250"
FT SITE 327
FT /note="Histone H3R2me0 binding"
FT /evidence="ECO:0000250"
FT SITE 476
FT /note="Required to confer preferential recognition of
FT cytosine over thymine"
FT /evidence="ECO:0000250"
FT SITE 486
FT /note="Required to discriminate between hemimethylated DNA
FT versus symmetrically methylated DNA"
FT /evidence="ECO:0000250"
FT SITE 488
FT /note="Required for affinity and specificity for 5-mCpG
FT sequence"
FT /evidence="ECO:0000250"
FT MOD_RES 76
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 91
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 93
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 95
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 161
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8VDF2"
FT MOD_RES 284
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 295
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 365
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 396
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 511
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8VDF2"
FT MOD_RES 542
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 631
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 641
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT MOD_RES 648
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8VDF2"
FT MOD_RES 751
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT CROSSLNK 276
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT CROSSLNK 382
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT CROSSLNK 542
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
FT CROSSLNK 656
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96T88"
SQ SEQUENCE 774 AA; 87449 MW; C2FB3112F2D2EF9E CRC64;
MWIQVRTMDG KETHTVNSLS RLTKVQELRK KIEELFHVEP QLQRLFYRGK QMEDGHTLFD
YDVRLNDTIQ LLVRQSLALP LSTKERDSEL SDSDSGYGVG HSESDKSSTH GEGTADGDDK
TVWEDTDLGL YKVNEYVDVR DNIFGAWFEA QVVQVQKKAL SEEEPCSSSA IMAPEDDIMY
HIKYDDYPEH GVDIVKAKNV RARARTVIPW EDLEVGQVVM ANYNVDYPRK RGFWYDVEIC
RKRQTRTARE LYGNVMLLND SQLNNCRIIF VDEVLKIELP NERSPLIGSP SRRKSGPSCQ
YCKDDENKPC RKCACHICGG REAPEKQVLC DECDMAFHLY CLQPPLTCVP PEPEWYCPSC
RTDSSEVVQA GEKLKKSKKK AKMASATSSS RRDWGKGMAC VGRTTECTIV PANHFGPIPG
VPVGTMWRFR VQVSESGVHR PHVAGIHGRS NDGAYSLVLA GGYEDDVDNG NFFTYTGSGG
RDLSGNKRTA GQSSDQKLTN NNRALALNCH SPINEKGAEA EDWRQGKPVR VVRNMKGGKH
SKYAPAEGNR YDGIYKVVKY WPEKGKSGFI VWRYLLRRDD TEPEPWTREG KDRTRQLGLT
MQYPEGYLEA LANKEKNRKR PAKALEQGPS SSKIGKSKRK STGPATTSPR VSKKSKLEPY
TLPLQQANLI KEDKGNAKLW DDVLSSLQDG PYQIFLSKVK EAFQCICCQE LVFRPVTTVC
QHNVCKDCLD RSFRAQVFSC PACRYDLDHS SPTRVNQPLQ TILNQLFPGY GSGR
