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FLASH GENE
Symbol DTL contributors: mct/npt - updated : 23-03-2013
HGNC name denticleless E3 ubiquitin protein ligase homolog (Drosophila)
HGNC id 30288
Location 1q32.3      Physical location : 212.208.918 - 212.278.186
Synonym name
  • retinoic acid-regulated nuclear matrix associated protein
  • RA-regulated nuclear matrix-associated protein
  • Ddb1- and Cul4-associated factor 2
  • chromatin licensing and DNA replication factor 2
  • lethal(2) denticleless protein homolog
  • E3 ubiquitin ligase called CRL4
  • Synonym symbol(s) L2DTL, RAMP, CDT2, DCAF2, CDW1, CRL4
    DNA
    TYPE functioning gene
    STRUCTURE 69.27 kb     15 Exon(s)
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    15 - 4428 79.3 730 - 2008 1854205
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunethymus   highly
    Reproductivefemale systemuteruscervix highly
     male systemtestis  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    Text placenta, all fetal tissues
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • WD 40 repeat domain
  • serine-threonine domain
  • HOMOLOGY
    interspecies ortholog to Drosophila lethal (2) denticleless, l(2)dtl
    Homologene
    FAMILY
  • WD repeat cdt2 family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus
    text
  • nucleus in the interphase
  • cytoplasm in the metaphase
  • located to the nucleus in interphase and centered to centrosomes, with colocalization of gamma-tubulin and Aurora-A, throughout the cell cycle
  • basic FUNCTION
  • involved in the proliferation of embryonal carcinoma cells
  • playing an important role in growth of breast cancer cells
  • plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation
  • functions as the substrate recruiting factor for CDKN1A to the rest of the CRL4 ubiquitin ligase complex
  • recognizes an unusual degron, which is assembled specifically on chromatin via the binding of a specialized PIP box to PCNA
  • central role of DTL-dependent cell-cycle regulation of SETD8 for the maintenance of a stable epigenetic state essential for cell viability
  • couples proteolysis to DNA synthesis via an unusual mechanism that involves display of substrate degrons on the DNA polymerase processivity factor PCNA
  • master regulator that prevents rereplication in S phase
  • its function is coupled to replication and repair because it only ubiquitinates substrates that associate with chromatin-bound PCNA
  • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • CUL4A/DTL E3 ubiquitin ligase plays an essential role in DNA replication origin licensing directing degradation of several licensing factors at the G1/S transition in order to prevent DNA re-replication
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • retinoic acid
  • PCNA promotes the DNA damage-induced degradation of the replication initiation factor CDT1 via the DTL E3 ubiquitin ligase complex
  • is a substrates of CDT1
  • DTL-dependent destruction of SETD8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis
  • during the DNA damage response, SETD8 interaction with PCNA through a specialized "PIP degron" domain targets it for PCNA-coupled DTL-dependent proteolysis
  • SETD8 is targeted for degradation during S phase by the DTL ubiquitin ligase in a proliferating cell nuclear antigen (PCNA)-dependent manner
  • DTL and WDHD1 play an essential role in the regulation of KAT2A protein stability
  • targets the activated form of CHEK1 for destruction in the nucleoplasm rather than on chromatin and that this occurs in a PCNA-independent manner
  • FBXO11 interacts with DTL, and recruits DTL to the SCF(FBXO11)complex to promote its proteasomal degradation
  • cell & other
    REGULATION
    repressed by FBXO11, that promotes the degradation of DTL during an unperturbed cell cycle to promote efficient progression through S and G 2/M phases of the cell cycle (PMID;
    Phosphorylated by ATR (ATR, activated after DNA damage, phosphorylates DTL and promotes the rapid degradation of CDT1 after UV irradiation in the G1 phase of the cell cycle)
    Other COP9/Signalosome regulates DTL stability through CUL4 deneddylation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in the majority of breast cancer cases
    tumoral     --over  
    associated with enhanced metastatic potential of hepatocellular carcinoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS