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Protein

Denticleless protein homolog

Gene

DTL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBXO18/FBH1 and KMT5A (PubMed:16861906, PubMed:16949367, PubMed:16964240, PubMed:17085480, PubMed:18703516, PubMed:18794347, PubMed:18794348, PubMed:19332548, PubMed:20129063, PubMed:23478441, PubMed:23478445, PubMed:23677613). CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication (PubMed:16861906, PubMed:16949367, PubMed:17085480). CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing (PubMed:18794348, PubMed:19332548). KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration (PubMed:23478445). Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the 'Lys-164' monoubiquitination of PCNA, thereby being involved in PCNA-dependent translesion DNA synthesis (PubMed:20129063, PubMed:23478441, PubMed:23478445, PubMed:23677613).12 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • DNA damage response, detection of DNA damage Source: Reactome
  • DNA replication Source: UniProtKB-KW
  • G2 DNA damage checkpoint Source: UniProtKB
  • protein monoubiquitination Source: UniProtKB
  • protein polyubiquitination Source: UniProtKB
  • regulation of cell cycle Source: UniProtKB
  • response to UV Source: UniProtKB
  • translesion synthesis Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: UniProtKB

Keywordsi

Biological processDNA damage, DNA replication, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-110314. Recognition of DNA damage by PCNA-containing replication complex.
SignaLinkiQ9NZJ0.
SIGNORiQ9NZJ0.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
Denticleless protein homolog
Alternative name(s):
DDB1- and CUL4-associated factor 2
Lethal(2) denticleless protein homolog
Retinoic acid-regulated nuclear matrix-associated protein
Gene namesi
Name:DTL
Synonyms:CDT2, CDW1, DCAF2, L2DTL, RAMP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:30288. DTL.

Subcellular locationi

GO - Cellular componenti

  • centrosome Source: UniProtKB
  • chromosome Source: UniProtKB-SubCell
  • Cul4A-RING E3 ubiquitin ligase complex Source: UniProtKB
  • Cul4B-RING E3 ubiquitin ligase complex Source: UniProtKB
  • cytosol Source: HPA
  • nuclear membrane Source: UniProtKB-SubCell
  • nucleolus Source: HPA
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB

Keywords - Cellular componenti

Chromosome, Cytoplasm, Cytoskeleton, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi246R → A: Blocks association with DDB1 and ubiquitination by DCX(DTL). No effect on ubiquitination by SCF(FBXO11). 2 Publications1
Mutagenesisi457D → A: Increases protein stability, but no effect on interaction with FBXO11 and polyubiquitination. Delays cell migration. 1 Publication1
Mutagenesisi462S → A: Blocks interaction with FBXO11 and ubiquitination, increasing protein stability. Delays cell migration. 1 Publication1
Mutagenesisi463N → A: No effect on interaction with FBXO11. Increases protein stability. 1 Publication1
Mutagenesisi464T → A: Blocks interaction with FBXO11 and increases protein stability. Not phosphorylated by CDK1 or CDK2. 1 Publication1
Mutagenesisi464T → D: Blocks interaction with FBXO11. 1 Publication1
Mutagenesisi465P → A: Inhibits phosphorylation on T-464. No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi466T → A: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi466T → D: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi467F → A: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi468S → A: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi468S → D: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi471T → A: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi471T → D: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi472S → A: No effect on interaction with FBXO11. 1 Publication1
Mutagenesisi472S → D: No effect on interaction with FBXO11. 1 Publication1

Organism-specific databases

DisGeNETi51514.
OpenTargetsiENSG00000143476.
PharmGKBiPA142671941.

Polymorphism and mutation databases

BioMutaiDTL.
DMDMi302393825.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002748671 – 730Denticleless protein homologAdd BLAST730

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1
Modified residuei196PhosphothreonineCombined sources1
Modified residuei410PhosphoserineCombined sources1
Modified residuei426PhosphoserineCombined sources1
Modified residuei464Phosphothreonine; by CDK1 and CDK21 Publication1
Modified residuei485PhosphoserineCombined sources1
Modified residuei490PhosphoserineCombined sources1
Modified residuei495PhosphoserineCombined sources1
Modified residuei512PhosphoserineCombined sources1
Modified residuei516PhosphothreonineCombined sources1
Modified residuei557PhosphoserineCombined sources1
Modified residuei676PhosphoserineCombined sources1
Modified residuei679PhosphoserineCombined sources1
Modified residuei684PhosphothreonineCombined sources1
Modified residuei702PhosphothreonineCombined sources1
Modified residuei717PhosphoserineCombined sources1

Post-translational modificationi

Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C). Autoubiquitinated through 'Lys-48'-polyubiquitin chains in a PCNA-independent reaction, allowing proteasomal turnover. Polyubiquitinated by SCF(FBXO11) when not phosphorylated, leading to its degradation. A tight regulation of the polyubiquitination by SCF(FBXO11) is involved in the control of different processes such as TGF-beta signaling, cell cycle progression and exit.3 Publications
Phosphorylated at Thr-464 by CDK1/Cyclin-B and CDK2/Cyclin-A but not by CDK2/Cyclin-E, MAPK1 or PLK1. Phosphorylation at Thr-464 inhibits the interaction with FBXO11 and decreases upon cell cycle exit induced by TGF-beta or serum starvation.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9NZJ0.
MaxQBiQ9NZJ0.
PaxDbiQ9NZJ0.
PeptideAtlasiQ9NZJ0.
PRIDEiQ9NZJ0.

PTM databases

iPTMnetiQ9NZJ0.
PhosphoSitePlusiQ9NZJ0.

Expressioni

Tissue specificityi

Expressed in placenta and testis, very low expression seen in skeletal muscle. Detected in all hematopoietic tissues examined, with highest expression in thymus and bone marrow. A low level detected in the spleen and lymph node, and barely detectable level in the peripheral leukocytes. RA treatment down-regulated the expression in NT2 cell.2 Publications

Developmental stagei

Expressed in all fetal tissues examined, included brain, lung, liver, and kidney. Protein levels peak at G1 and decrease through S-phase.2 Publications

Inductioni

Induced by TGF-beta, the up-regulation is immediate and transient.1 Publication

Gene expression databases

BgeeiENSG00000143476.
CleanExiHS_DTL.
ExpressionAtlasiQ9NZJ0. baseline and differential.
GenevisibleiQ9NZJ0. HS.

Organism-specific databases

HPAiHPA028016.
HPA032023.
HPA032031.

Interactioni

Subunit structurei

Component of the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)), at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1. Interacts with CDKN1A and CDT1. Interacts with FBXO11; SCF(FBXWO11) controls DTL stability but DCX(DTL) does not control FBXO11 stability.8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
DDB1Q165313EBI-1176075,EBI-350322

Protein-protein interaction databases

BioGridi119582. 66 interactors.
IntActiQ9NZJ0. 8 interactors.
STRINGi9606.ENSP00000355958.

Structurei

3D structure databases

ProteinModelPortaliQ9NZJ0.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati47 – 89WD 1Add BLAST43
Repeati96 – 135WD 2Add BLAST40
Repeati138 – 178WD 3Add BLAST41
Repeati214 – 253WD 4Add BLAST40
Repeati267 – 308WD 5Add BLAST42
Repeati313 – 354WD 6Add BLAST42
Repeati358 – 398WD 7Add BLAST41

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi168 – 171DDB1-binding motif4
Motifi197 – 203Nuclear localization signalSequence analysis7
Motifi243 – 246DDB1-binding motif4

Sequence similaritiesi

Belongs to the WD repeat cdt2 family.Curated

Keywords - Domaini

Repeat, WD repeat

Phylogenomic databases

eggNOGiKOG0321. Eukaryota.
ENOG410XRWK. LUCA.
GeneTreeiENSGT00530000064210.
HOVERGENiHBG057737.
InParanoidiQ9NZJ0.
KOiK11790.
OMAiICTYFHR.
OrthoDBiEOG091G04RK.
PhylomeDBiQ9NZJ0.
TreeFamiTF324483.

Family and domain databases

Gene3Di2.130.10.10. 1 hit.
InterProiView protein in InterPro
IPR015943. WD40/YVTN_repeat-like_dom.
IPR001680. WD40_repeat.
IPR019775. WD40_repeat_CS.
IPR017986. WD40_repeat_dom.
PfamiView protein in Pfam
PF00400. WD40. 5 hits.
SMARTiView protein in SMART
SM00320. WD40. 6 hits.
SUPFAMiSSF50978. SSF50978. 2 hits.
PROSITEiView protein in PROSITE
PS00678. WD_REPEATS_1. 2 hits.
PS50082. WD_REPEATS_2. 5 hits.
PS50294. WD_REPEATS_REGION. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NZJ0-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLFNSVLRQP QLGVLRNGWS SQYPLQSLLT GYQCSGNDEH TSYGETGVPV
60 70 80 90 100
PPFGCTFSSA PNMEHVLAVA NEEGFVRLYN TESQSFRKKC FKEWMAHWNA
110 120 130 140 150
VFDLAWVPGE LKLVTAAGDQ TAKFWDVKAG ELIGTCKGHQ CSLKSVAFSK
160 170 180 190 200
FEKAVFCTGG RDGNIMVWDT RCNKKDGFYR QVNQISGAHN TSDKQTPSKP
210 220 230 240 250
KKKQNSKGLA PSVDFQQSVT VVLFQDENTL VSAGAVDGII KVWDLRKNYT
260 270 280 290 300
AYRQEPIASK SFLYPGSSTR KLGYSSLILD STGSTLFANC TDDNIYMFNM
310 320 330 340 350
TGLKTSPVAI FNGHQNSTFY VKSSLSPDDQ FLVSGSSDEA AYIWKVSTPW
360 370 380 390 400
QPPTVLLGHS QEVTSVCWCP SDFTKIATCS DDNTLKIWRL NRGLEEKPGG
410 420 430 440 450
DKLSTVGWAS QKKKESRPGL VTVTSSQSTP AKAPRAKCNP SNSSPSSAAC
460 470 480 490 500
APSCAGDLPL PSNTPTFSIK TSPAKARSPI NRRGSVSSVS PKPPSSFKMS
510 520 530 540 550
IRNWVTRTPS SSPPITPPAS ETKIMSPRKA LIPVSQKSSQ AEACSESRNR
560 570 580 590 600
VKRRLDSSCL ESVKQKCVKS CNCVTELDGQ VENLHLDLCC LAGNQEDLSK
610 620 630 640 650
DSLGPTKSSK IEGAGTSISE PPSPISPYAS ESCGTLPLPL RPCGEGSEMV
660 670 680 690 700
GKENSSPENK NWLLAMAAKR KAENPSPRSP SSQTPNSRRQ SGKKLPSPVT
710 720 730
ITPSSMRKIC TYFHRKSQED FCGPEHSTEL
Length:730
Mass (Da):79,468
Last modified:August 10, 2010 - v3
Checksum:iCE8D54234D44F002
GO
Isoform 2 (identifier: Q9NZJ0-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     18-59: Missing.
     240-253: IKVWDLRKNYTAYR → FKSDFGFHWLYFIC
     254-730: Missing.

Note: No experimental confirmation available.
Show »
Length:211
Mass (Da):23,682
Checksum:i23E4B52CFC514F80
GO

Sequence cautioni

The sequence BAA91552 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAA91586 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti83S → P in BAA91355 (PubMed:14702039).Curated1
Sequence conflicti356L → F in BAF85032 (PubMed:14702039).Curated1
Sequence conflicti532I → T in BAA91552 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_062095425S → N. Corresponds to variant dbSNP:rs35137676Ensembl.1
Natural variantiVAR_030353436A → V6 PublicationsCorresponds to variant dbSNP:rs3135474Ensembl.1
Natural variantiVAR_030354694K → TCombined sources5 PublicationsCorresponds to variant dbSNP:rs6540718Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_02287918 – 59Missing in isoform 2. 1 PublicationAdd BLAST42
Alternative sequenceiVSP_022880240 – 253IKVWD…YTAYR → FKSDFGFHWLYFIC in isoform 2. 1 PublicationAdd BLAST14
Alternative sequenceiVSP_022881254 – 730Missing in isoform 2. 1 PublicationAdd BLAST477

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF345896 mRNA. Translation: AAK54706.1.
DQ641253 mRNA. Translation: ABG23317.1.
AF195765 mRNA. Translation: AAF35182.1.
AK000742 mRNA. Translation: BAA91355.1.
AK001206 mRNA. Translation: BAA91552.1. Different initiation.
AK001261 mRNA. Translation: BAA91586.1. Different initiation.
AK027651 mRNA. Translation: BAB55267.1.
AK292343 mRNA. Translation: BAF85032.1.
AL606468, AC092814, AL592297 Genomic DNA. Translation: CAH70697.1.
AL592297, AC092814, AL606468 Genomic DNA. Translation: CAH73803.1.
CH471100 Genomic DNA. Translation: EAW93395.1.
CH471100 Genomic DNA. Translation: EAW93397.1.
BC033540 mRNA. Translation: AAH33540.1.
BC033297 mRNA. Translation: AAH33297.1.
CCDSiCCDS1502.1. [Q9NZJ0-1]
RefSeqiNP_001273158.1. NM_001286229.1.
NP_057532.3. NM_016448.3.
UniGeneiHs.656473.

Genome annotation databases

EnsembliENST00000366991; ENSP00000355958; ENSG00000143476. [Q9NZJ0-1]
GeneIDi51514.
KEGGihsa:51514.
UCSCiuc009xdc.5. human. [Q9NZJ0-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF345896 mRNA. Translation: AAK54706.1.
DQ641253 mRNA. Translation: ABG23317.1.
AF195765 mRNA. Translation: AAF35182.1.
AK000742 mRNA. Translation: BAA91355.1.
AK001206 mRNA. Translation: BAA91552.1. Different initiation.
AK001261 mRNA. Translation: BAA91586.1. Different initiation.
AK027651 mRNA. Translation: BAB55267.1.
AK292343 mRNA. Translation: BAF85032.1.
AL606468, AC092814, AL592297 Genomic DNA. Translation: CAH70697.1.
AL592297, AC092814, AL606468 Genomic DNA. Translation: CAH73803.1.
CH471100 Genomic DNA. Translation: EAW93395.1.
CH471100 Genomic DNA. Translation: EAW93397.1.
BC033540 mRNA. Translation: AAH33540.1.
BC033297 mRNA. Translation: AAH33297.1.
CCDSiCCDS1502.1. [Q9NZJ0-1]
RefSeqiNP_001273158.1. NM_001286229.1.
NP_057532.3. NM_016448.3.
UniGeneiHs.656473.

3D structure databases

ProteinModelPortaliQ9NZJ0.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119582. 66 interactors.
IntActiQ9NZJ0. 8 interactors.
STRINGi9606.ENSP00000355958.

PTM databases

iPTMnetiQ9NZJ0.
PhosphoSitePlusiQ9NZJ0.

Polymorphism and mutation databases

BioMutaiDTL.
DMDMi302393825.

Proteomic databases

EPDiQ9NZJ0.
MaxQBiQ9NZJ0.
PaxDbiQ9NZJ0.
PeptideAtlasiQ9NZJ0.
PRIDEiQ9NZJ0.

Protocols and materials databases

DNASUi51514.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000366991; ENSP00000355958; ENSG00000143476. [Q9NZJ0-1]
GeneIDi51514.
KEGGihsa:51514.
UCSCiuc009xdc.5. human. [Q9NZJ0-1]

Organism-specific databases

CTDi51514.
DisGeNETi51514.
GeneCardsiDTL.
H-InvDBHIX0020157.
HGNCiHGNC:30288. DTL.
HPAiHPA028016.
HPA032023.
HPA032031.
MIMi610617. gene.
neXtProtiNX_Q9NZJ0.
OpenTargetsiENSG00000143476.
PharmGKBiPA142671941.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0321. Eukaryota.
ENOG410XRWK. LUCA.
GeneTreeiENSGT00530000064210.
HOVERGENiHBG057737.
InParanoidiQ9NZJ0.
KOiK11790.
OMAiICTYFHR.
OrthoDBiEOG091G04RK.
PhylomeDBiQ9NZJ0.
TreeFamiTF324483.

Enzyme and pathway databases

UniPathwayiUPA00143.
ReactomeiR-HSA-110314. Recognition of DNA damage by PCNA-containing replication complex.
SignaLinkiQ9NZJ0.
SIGNORiQ9NZJ0.

Miscellaneous databases

GeneWikiiDTL_(gene).
GenomeRNAii51514.
PROiQ9NZJ0.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000143476.
CleanExiHS_DTL.
ExpressionAtlasiQ9NZJ0. baseline and differential.
GenevisibleiQ9NZJ0. HS.

Family and domain databases

Gene3Di2.130.10.10. 1 hit.
InterProiView protein in InterPro
IPR015943. WD40/YVTN_repeat-like_dom.
IPR001680. WD40_repeat.
IPR019775. WD40_repeat_CS.
IPR017986. WD40_repeat_dom.
PfamiView protein in Pfam
PF00400. WD40. 5 hits.
SMARTiView protein in SMART
SM00320. WD40. 6 hits.
SUPFAMiSSF50978. SSF50978. 2 hits.
PROSITEiView protein in PROSITE
PS00678. WD_REPEATS_1. 2 hits.
PS50082. WD_REPEATS_2. 5 hits.
PS50294. WD_REPEATS_REGION. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiDTL_HUMAN
AccessioniPrimary (citable) accession number: Q9NZJ0
Secondary accession number(s): A8K8H8
, D3DT98, Q5VT77, Q96SN0, Q9NW03, Q9NW34, Q9NWM5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 6, 2007
Last sequence update: August 10, 2010
Last modified: March 15, 2017
This is version 140 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.