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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	24.28 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed variant 1 - splicing 717 isoform 1 - 238 highly in brain and heart 2002 11852074 also called DDB2 ID1 dominant negative inhibitor of DNA repair, which is probably due to disruption of complex formation between DDB1 and DDB2-WT and of DDB1 nuclear import not part of the damaged DNA-protein complex NM_000107 10 - 1870 NP_000098 48 427 - 2002 11852074 interacting with ID1 and itself variant 2 - splicing 960 isoform 2 - 156 - 2002 11852074 also called DDB2 ID2 dominant negative inhibitor of DNA repair, which is probably due to disruption of complex formation between DDB1 and DDB2-WT and of DDB1 nuclear import not part of the damaged DNA-protein complex variant 3 - splicing 1092 isoform 3 - 363 - 2002 11852074 also called DDB2 ID3 variant 4 - splicing 1106 isoform 4 - 244 - 2002 11852074 also called DDB2 ID4 NM_001300734 6 - 1303 NM_001300734 - 238 - 2002 11852074 variant (D1)

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver           stomach       highly Endocrine pancreas         Lymphoid/Immune tonsils       highly Reproductive female system uterus cervix   highly Respiratory lung

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cell lineage

cell lines

fluid/secretion

at STAGE

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed cancer reproductive prostate 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