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FLASH GENE
Symbol DDB2 contributors: mct - updated : 04-12-2018
HGNC name damage-specific DNA binding protein 2, 48kDa
HGNC id 2718
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • G protein beta with five WD40 repeats
    • conjugated Other
    mono polymer heteromer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • WD repeat DDB2/WDR76 family
    • CATEGORY regulatory , DNA associated
    SUBCELLULAR LOCALIZATION     plasma membrane,junction
        intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • pyrimidine-dimer repair, global genomic nucleotide excision repair (NER) and transcription-coupled repair (TCR) of oxidative lesions
  • participates in NER by regulating the cellular levels of CDKN1A
  • involved in nucleotide excision repair as well as in other biological processes in normal cells, including transcription and cell cycle regulation
  • can play a role as oncogene and may become a promising candidate as a predictive marker in breast cancer
  • having an intrinsic damaged DNA binding activity but neither DDB2 nor complexes that contain DDB2 (UV-DDB, CUL4A, and COP9) participate in nucleotide excision repair carried out by the six-factor human excision nuclease
  • regulates negatively the constitutive expression of the SOD2 gene in breast cancer cells and exerts, at least in part, a control of breast cacner cell growth
  • transcriptional regulator
  • upon oxidative stress, functions in a positive feedback loop by repressing the antioxidant genes to cause persistent accumulation of ROS and induce premature senescence
  • in addition to stimulating NER, plays a significant role in terminating DNA damage checkpoint, allowing cells with extensive DNA damage to undergo apoptosis
  • likely has evolved to participate in transcriptional repression of the antioxidant genes to ensure that cells harboring DNA damage do not replicate
  • is essential for efficient recognition and subsequent removal of ultraviolet (UV)-induced DNA lesions by nucleotide excision repair (NER)
  • DDB2 and XPC, two early UV damage recognition factors, are required for the damage-specific ATR and ATM recruitment and phosphorylation
  • DDB2 has been implicated in promoting cell-cycle progression by regulating gene expression
  • is a protein playing an essential role in the lesion recognition step of the global genome sub-pathway of nucleotide excision repair (GG-NER) process
  • DDB2 exhibits a high affinity toward UV-damaged DNA, and it is involved in the initial steps of global genome nucleotide excision repair
  • participates in both nucleotide excision repair and mRNA transcription
  • is modified by SUMOylation upon UV irradiation, and this post-translational modification plays an important role in the initial recognition and processing of UVR (UV radiation)-induced DNA damage occurring within the context of chromatin
  • is both a partner and regulator of WNT signaling, with an important role in suppressing colon cancer development
    • CELLULAR PROCESS cell life, cell death/apoptosis
    nucleotide, repair, nucleotide excision repair
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    text modulator of UV-induced apoptosis
    PATHWAY
    metabolism
    signaling
    nucleotide-excision repair
    a component
  • DDB is a heterodimeric complex comprising DDB1 and DDB2 subunits and binds to a wide spectrum of DNA lesions
  • at least four forms in the cell: monomeric DDB2, DDB1-DDB2 heterodimer (UV-DDB), and as a protein associated with both the Cullin 4A (CUL4A) complex and the COP9 signalosome
  • DDB1-DDB2 complex serves in the initial detection of UV lesions
    • INTERACTION
    DNA binding tightly to damaged DNA after UV irradiation
    RNA
    small molecule
    protein
  • CUL4A (target of CUL4A)
  • interaction with XPA (the physical interaction between DDB1 and 2 and XPA plays an important role in the DDB-mediated NER reaction)
  • is a novel androgen receptor (AR)-interacting protein, mediating contact with AR and CUL4A-DDB1 complex for AR ubiquitination/degradation
  • PARP1 is a novel DDB2-associated factor
  • PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of CHD1L
  • is a novel regulator of NFKB1 and breast tumor invasion
  • DDB2 is involved in the CUL4-DDB1 complex mediating CDKN1A degradation
  • DDB2 is a PCNA-binding protein, and that this association is required for DDB2 proteolytic degradation
  • XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacity
  • UVRAG is a regulator of CRL4(DDB2)-mediated NER, suggesting that its expression levels may influence melanoma predisposition
  • DDB2 is critical for chromatin association of XRCC5/XRCC6 in the absence of DNA damage and provide evidence that XRCC5/XRCC6 are functional partners of DDB2 in its transcriptional stimulatory activity
  • PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote nucleotide excision repair (GG-NER)
  • is critical for CTNNB1-mediated activation of RNF43, which restricts WNT signaling by removing WNT receptors from the cell surface
  • DDB2, functioning as a transcription repressor, can abrogate ovarian Cancer stem cells (CSCs) properties by downregulating ALDH1A1 expression
    • cell & other
  • regulating the pool of hepatitis B virus through interaction with the viral X protein
    • REGULATION
    activated by TP53 (directly)
    repressed by proteosomal degradation after UV-irradiation
    ASSOCIATED DISORDERS
    corresponding disease(s) XPE
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional        
    in xeroderma pigmentosum, type E
    Susceptibility to progressive supranuclear palsy (PSP)
    Variant & Polymorphism SNP increasing the risk of progressive supranuclear palsy (PSP)
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductiveprostate
    may be a potential regimen for prostate cancer treatment, especially in androgen-refractory patients harboring high amount of AR who cannot be cured by androgen ablation
    ANIMAL & CELL MODELS
  • DDB2–/– mice are susceptible to UV-induced skin carcinogenesis
  • mice genetically deficient in Ddb2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of the Wnt receptor-expressing cells and greater activation of the downstream Wnt pathway