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The UniProt accession Q92466 corresponds to human DDB2 (DNA damage-binding protein 2; also called DDB p48 / UV-DDB2 / XPE/p48), a WD40-repeat protein that heterodimerizes with DDB1 to form UV-DDB and functions in DNA damage recognition. Structural work defines an N-terminal helix–loop–helix (HLH) used for DDB1 association and a 7-bladed WD40 β-propeller that mediates DNA binding, matching the WD-repeat family/domain expectations given in the prompt. (scrima2008structuralbasisof pages 2-3, jia2011bimodalmechanismof pages 20-24)
A key initiating step of mammalian GG-NER is lesion detection in chromatin and recruitment of the canonical sensor XPC. DDB2, as part of the DDB1–DDB2 (UV-DDB) complex, functions as an early damage-recognition factor that binds UV photolesions and helps promote recruitment/“handoff” to XPC, particularly for lesions that XPC detects inefficiently. (matsumoto2015functionalregulationof pages 1-2, clement2010dynamictwostagemechanism pages 22-27, jia2011bimodalmechanismof pages 44-49)
DDB2 also acts as a substrate receptor within a cullin-RING E3 ubiquitin ligase CRL4\^DDB2 (CUL4–RBX1–DDB1–DDB2). Upon binding to UV-damaged chromatin, this ligase can ubiquitinate multiple proteins at damage sites (including DDB2 itself, XPC, and histones), coupling lesion recognition to ubiquitin signaling and chromatin remodeling during repair initiation. (matsumoto2015functionalregulationof pages 1-2)
Lesion types recognized. DDB2 is reported to recognize UV-induced lesions, including cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs), and it has been described to bind additional abnormal DNA structures including mismatches, apurinic/apyrimidinic (AP) sites, and compound lesions. (matsumoto2015functionalregulationof pages 12-13, jia2011bimodalmechanismof pages 20-24, clement2010dynamictwostagemechanism pages 22-27)
Structural basis of binding. Crystal structures of the human DDB1–DDB2 complex bound to damaged DNA (including a 6-4PP and an abasic site mimic, THF) show that DDB2’s WD40 β-propeller mediates DNA binding and recognition. DDB2 contacts ~7 bp around the lesion and induces an approximately 40° DNA kink with local strand separation. The DDB1–DDB2 interface is large (reported ~3900 Ų), consistent with stable heterodimerization. (Scrima et al., Cell, Dec 2008, https://doi.org/10.1016/j.cell.2008.10.045) (scrima2008structuralbasisof pages 2-3)
In chromatin, DDB2 rapidly translocates to UV lesions and associates with damaged chromatin ahead of XPC, consistent with a model where UV-DDB serves as an initial lesion sensor and organizer that facilitates subsequent XPC engagement. (jia2011bimodalmechanismof pages 20-24, jia2011bimodalmechanismof pages 44-49)
One mechanistic model emphasizes that DDB2 promotes GG-NER by both (i) ubiquitin-linked mechanisms that affect XPC behavior in chromatin and (ii) ubiquitin-independent transient interactions that help XPC productively engage lesions. (jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 44-49)
DDB2’s function is primarily nuclear, where it rapidly relocates to UV-damaged chromatin and binds lesions with high affinity relative to other NER factors, consistent with its role in early damage recognition in GG-NER. (jia2011bimodalmechanismof pages 20-24, jia2011bimodalmechanismof pages 44-49)
Poly-ubiquitination suppresses DNA binding and promotes turnover. Experimental work shows that while unmodified DDB2 binds UV-damaged DNA, poly-ubiquitinated DDB2 is recovered predominantly unbound and poly-ubiquitination abrogates damaged-DNA binding, promoting proteasomal degradation after UV exposure. (Matsumoto et al., Nucleic Acids Research, Jan 2015, https://doi.org/10.1093/nar/gkv038) (matsumoto2015functionalregulationof pages 5-7, matsumoto2015functionalregulationof pages 1-2)
XPC-dependent stabilization. Endogenous DDB2 can be stabilized after UV as a function of XPC expression: XPC competitively suppresses DDB2 ubiquitination in vitro, and this protection is enhanced by centrin-2, supporting a model in which XPC enables DDB2 to initiate multiple rounds of repair by limiting DDB2 degradation. (matsumoto2015functionalregulationof pages 1-2)
Additional regulatory nodes. Regulatory influences described in this framework include COP9 signalosome–linked control of CRL4 ligase activity, and other modulators (e.g., p38 MAPK and PARP1-dependent stabilization described in the same mechanistic context). (matsumoto2015functionalregulationof pages 12-13)
A chromatin-centric model reported that ~90% of 6-4PPs occur in MNase-sensitive chromatin and ~75% of 6-4PPs are removed within the first hour in wild-type cells, with DDB2 loss (XP-E) associated with delayed early 6-4PP repair; XP-E contexts were described as having ~50% CPD excision efficiency in the cited model. (jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 20-24)
A 2024 study in pancreatic ductal adenocarcinoma (PDAC) cell lines (T3M4 and Capan-2) reported that higher DDB2 expression is associated with radioresistance, including fewer residual DNA damage markers after irradiation (γH2AX foci differences with reported p-values). The work proposes DDB2 as a predictive biomarker for radiotherapy response and suggests that low DDB2 expression may enhance radiosensitization by olaparib in certain PDAC contexts. (Dardare et al., Cell Death Discovery, Sep 2024, https://doi.org/10.1038/s41420-024-02188-9) (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6)
Mechanistically, the same study links DDB2 to Chk1/Chk2 phosphorylation, G2/M arrest, and increased PARP1 expression/activity, connecting DDB2 to DNA damage response circuitry beyond canonical UV-lesion GG-NER. (dardare2024ddb2expressionlights pages 6-7, dardare2024ddb2expressionlights pages 6-6)
A 2024 BMC Cancer study examined a DDB2 mutant defective in PCNA binding (DDB2\u2009PCNA−) in UV-damaged human cells and reported enhanced EMT-like changes and increased NF-κB pathway activity, including increased nuclear localization of NF-κB and altered EMT marker behavior. The study also reported a detectable DDB2–NF-κB interaction that was stronger with the PCNA-binding-deficient DDB2 mutant, implicating the DDB2–PCNA interaction in restraining EMT/NF-κB programs after UV damage in this model. (Perucca et al., BMC Cancer, May 2024, https://doi.org/10.1186/s12885-024-12368-6) (perucca2024epithelialtomesenchymaltransitionand pages 11-14, perucca2024epithelialtomesenchymaltransitionand pages 1-2)
A 2024 Scientific Reports study advanced DDB2 as a protein biomarker (with BAX) for acute radiation exposure using ELISA and machine-learning models in human and non-human primate (NHP) blood.
These reported performance statistics support DDB2’s practical deployment in multi-marker biodosimetry pipelines and highlight a real-world implementation path distinct from DDB2’s original NER context. (kanagaraj2024baxandddb2 pages 1-2, kanagaraj2024baxandddb2 pages 3-6)
Recent PDAC findings position DDB2 expression as a candidate biomarker for stratifying radiotherapy response and potentially PARP-inhibitor radiosensitization strategies in preclinical PDAC models. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6)
Collectively, the strongest, most direct mechanistic evidence supports DDB2’s primary role as a WD40-repeat DNA lesion sensor in GG-NER, functioning through UV-DDB to recognize UV photolesions (notably 6-4PPs and CPDs) and to coordinate lesion processing by coupling detection to XPC recruitment/handoff and CRL4\^DDB2 ubiquitin signaling in chromatin. (scrima2008structuralbasisof pages 2-3, matsumoto2015functionalregulationof pages 1-2, clement2010dynamictwostagemechanism pages 22-27)
Recent 2024 studies extend DDB2’s translational relevance into (i) radiotherapy/PARP inhibitor response hypotheses in PDAC models and (ii) an applied biodosimetry setting where DDB2 protein levels contribute to high-accuracy classification and dose reconstruction. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6, kanagaraj2024baxandddb2 pages 3-6)
The following table consolidates the evidence-backed functional annotation.
| Category | Summary |
|---|---|
| Identity/domains | Human DDB2 is the DNA damage-binding protein 2 encoded by DDB2 (UniProt Q92466), a WD40-family protein that contains an N-terminal helix-loop-helix region for DDB1 association and a 7-bladed WD40 β-propeller that mediates DNA binding; DDB2 is unstable/poorly soluble without DDB1. (scrima2008structuralbasisof pages 2-3, jia2011bimodalmechanismof pages 20-24) |
| Core molecular function | DDB2 is the lesion-recognition subunit of the UV-DDB complex and acts early in global-genome nucleotide excision repair (GG-NER) by binding UV-damaged DNA and facilitating recruitment/transfer to XPC, especially for lesions that XPC recognizes inefficiently on its own. (matsumoto2015functionalregulationof pages 1-2, clement2010dynamictwostagemechanism pages 22-27, jia2011bimodalmechanismof pages 44-49) |
| Lesion specificity | DDB2 binds strongly to UV photolesions, particularly 6-4 photoproducts and also CPDs; reported substrates additionally include abasic/AP sites, mismatches, and compound lesions. Structural work showed recognition of a 6-4PP and an abasic-site mimic (THF). (scrima2008structuralbasisof pages 2-3, matsumoto2015functionalregulationof pages 12-13, jia2011bimodalmechanismof pages 20-24, clement2010dynamictwostagemechanism pages 22-27) |
| Key complexes/partners | DDB2 forms a heterodimer with DDB1 (UV-DDB) and serves as the substrate receptor in the CRL4^DDB2 ubiquitin ligase with CUL4A/RBX1; functionally important partners include XPC, centrin-2, COP9 signalosome, PARP1, p97 segregase, and chromatin substrates such as histones. (scrima2008structuralbasisof pages 2-3, matsumoto2015functionalregulationof pages 12-13, matsumoto2015functionalregulationof pages 5-7, matsumoto2015functionalregulationof pages 1-2) |
| Post-translational regulation | UV-damage binding activates CRL4^DDB2-dependent ubiquitination of DDB2, XPC, and histones; mono-ubiquitination can be compatible with damage binding, whereas poly-ubiquitination abrogates DDB2 damaged-DNA binding and promotes proteasomal degradation. XPC competitively suppresses DDB2 ubiquitination and stabilizes endogenous DDB2 after UV; regulation also involves COP9/neddylation, p38 MAPK, and PARP1-mediated stabilization. (matsumoto2015functionalregulationof pages 12-13, matsumoto2015functionalregulationof pages 5-7, matsumoto2015functionalregulationof pages 1-2) |
| Cellular localization | DDB2 functions primarily in the nucleus on UV-damaged chromatin, where it rapidly translocates after UV exposure, binds lesions ahead of XPC, and accumulates at chromatin-associated repair sites. (jia2011bimodalmechanismof pages 20-24, jia2011bimodalmechanismof pages 44-49) |
| Pathways | DDB2 operates in global-genome NER, coupling lesion detection to chromatin remodeling and ubiquitin signaling; its activity promotes lesion handoff to XPC and helps organize repair in accessible chromatin regions. Recent PDAC work also links DDB2 to ionizing-radiation responses via checkpoint signaling and PARP1-associated DSB repair processes. (jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 44-49, dardare2024ddb2expressionlights pages 6-7, dardare2024ddb2expressionlights pages 6-6) |
| 2023-2024 developments | Recent studies expand DDB2 biology beyond canonical UV repair: in PDAC, higher DDB2 promoted radioresistance, Chk1/Chk2 phosphorylation, PARP1 activity, and reduced residual γH2AX after irradiation; in tumor-biology models, reduced or altered DDB2 regulation was linked to EMT/NF-κB programs and metastasis-associated phenotypes. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-7, perucca2024epithelialtomesenchymaltransitionand pages 11-14, perucca2024epithelialtomesenchymaltransitionand pages 1-2, perucca2024epithelialtomesenchymaltransitionand pages 14-15) |
| Applications/biomarkers | DDB2 is being investigated as a predictive biomarker for radiotherapy response and olaparib radiosensitization in PDAC, and as a protein biomarker in radiation biodosimetry assays; recent cancer studies also support its relevance as a metastasis/EMT-associated regulatory node in some tumor contexts. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-7) |
| Quantitative stats | Structural studies reported DDB2-induced ~40° DNA kinking, ~2100 Ų DNA-contact surface, and ~3900 Ų DDB1-DDB2 interface; one mechanistic model reported ~90% of 6-4PPs in MNase-sensitive chromatin and ~75% removed within 1 h in wild-type cells, with ~50% CPD excision efficiency in XP-E settings. In a 2024 biodosimetry assay using DDB2+BAX, classification accuracy was 97.92% in human and 96% in NHP blood, with dose-prediction R² values of 0.79 and 0.80, respectively. (scrima2008structuralbasisof pages 2-3, jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 20-24) |
Table: This table summarizes the evidence-backed functional annotation of human DDB2 (UniProt Q92466), covering its identity, molecular role in GG-NER, regulation, recent 2023-2024 developments, and emerging biomarker applications. It is useful as a compact reference linking each claim to specific retrieved evidence contexts.
References
(scrima2008structuralbasisof pages 2-3): Andrea Scrima, Renata Koníčková, Bryan K. Czyzewski, Yusuke Kawasaki, Philip D. Jeffrey, Regina Groisman, Yoshihiro Nakatani, Shigenori Iwai, Nikola P. Pavletich, and Nicolas H. Thomä. Structural basis of uv dna-damage recognition by the ddb1–ddb2 complex. Cell, 135:1213-1223, Dec 2008. URL: https://doi.org/10.1016/j.cell.2008.10.045, doi:10.1016/j.cell.2008.10.045. This article has 546 citations and is from a highest quality peer-reviewed journal.
(jia2011bimodalmechanismof pages 20-24): Jia Fei. Bimodal mechanism of dna repair stimulation by ddb2 (xpe) in chromatin. ArXiv, 2011. URL: https://doi.org/10.5167/uzh-164006, doi:10.5167/uzh-164006. This article has 0 citations.
(matsumoto2015functionalregulationof pages 1-2): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thomä, and Kaoru Sugasawa. Functional regulation of the dna damage-recognition factor ddb2 by ubiquitination and interaction with xeroderma pigmentosum group c protein. Nucleic Acids Research, 43:1700-1713, Jan 2015. URL: https://doi.org/10.1093/nar/gkv038, doi:10.1093/nar/gkv038. This article has 69 citations and is from a highest quality peer-reviewed journal.
(clement2010dynamictwostagemechanism pages 22-27): Flurina C. Clement, Ulrike Camenisch, Jia Fei, Nina Kaczmarek, Nadine Mathieu, and Hanspeter Naegeli. Dynamic two-stage mechanism of versatile dna damage recognition by xeroderma pigmentosum group c protein. Mutation research, 685 1-2:21-8, Mar 2010. URL: https://doi.org/10.1016/j.mrfmmm.2009.08.005, doi:10.1016/j.mrfmmm.2009.08.005. This article has 56 citations and is from a peer-reviewed journal.
(jia2011bimodalmechanismof pages 44-49): Jia Fei. Bimodal mechanism of dna repair stimulation by ddb2 (xpe) in chromatin. ArXiv, 2011. URL: https://doi.org/10.5167/uzh-164006, doi:10.5167/uzh-164006. This article has 0 citations.
(matsumoto2015functionalregulationof pages 12-13): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thomä, and Kaoru Sugasawa. Functional regulation of the dna damage-recognition factor ddb2 by ubiquitination and interaction with xeroderma pigmentosum group c protein. Nucleic Acids Research, 43:1700-1713, Jan 2015. URL: https://doi.org/10.1093/nar/gkv038, doi:10.1093/nar/gkv038. This article has 69 citations and is from a highest quality peer-reviewed journal.
(jia2011bimodalmechanismof pages 122-126): Jia Fei. Bimodal mechanism of dna repair stimulation by ddb2 (xpe) in chromatin. ArXiv, 2011. URL: https://doi.org/10.5167/uzh-164006, doi:10.5167/uzh-164006. This article has 0 citations.
(matsumoto2015functionalregulationof pages 5-7): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thomä, and Kaoru Sugasawa. Functional regulation of the dna damage-recognition factor ddb2 by ubiquitination and interaction with xeroderma pigmentosum group c protein. Nucleic Acids Research, 43:1700-1713, Jan 2015. URL: https://doi.org/10.1093/nar/gkv038, doi:10.1093/nar/gkv038. This article has 69 citations and is from a highest quality peer-reviewed journal.
(dardare2024ddb2expressionlights pages 1-2): Julie Dardare, Andréa Witz, Margaux Betz, Aurélie François, Laureline Lamy, Marie Husson, Jessica Demange, Marie Rouyer, Aurélien Lambert, Jean-Louis Merlin, Pauline Gilson, and Alexandre Harlé. Ddb2 expression lights the way for precision radiotherapy response in pdac cells, with or without olaparib. Cell Death Discovery, Sep 2024. URL: https://doi.org/10.1038/s41420-024-02188-9, doi:10.1038/s41420-024-02188-9. This article has 10 citations and is from a peer-reviewed journal.
(dardare2024ddb2expressionlights pages 6-6): Julie Dardare, Andréa Witz, Margaux Betz, Aurélie François, Laureline Lamy, Marie Husson, Jessica Demange, Marie Rouyer, Aurélien Lambert, Jean-Louis Merlin, Pauline Gilson, and Alexandre Harlé. Ddb2 expression lights the way for precision radiotherapy response in pdac cells, with or without olaparib. Cell Death Discovery, Sep 2024. URL: https://doi.org/10.1038/s41420-024-02188-9, doi:10.1038/s41420-024-02188-9. This article has 10 citations and is from a peer-reviewed journal.
(dardare2024ddb2expressionlights pages 6-7): Julie Dardare, Andréa Witz, Margaux Betz, Aurélie François, Laureline Lamy, Marie Husson, Jessica Demange, Marie Rouyer, Aurélien Lambert, Jean-Louis Merlin, Pauline Gilson, and Alexandre Harlé. Ddb2 expression lights the way for precision radiotherapy response in pdac cells, with or without olaparib. Cell Death Discovery, Sep 2024. URL: https://doi.org/10.1038/s41420-024-02188-9, doi:10.1038/s41420-024-02188-9. This article has 10 citations and is from a peer-reviewed journal.
(perucca2024epithelialtomesenchymaltransitionand pages 11-14): Paola Perucca, Elisabetta Bassi, Martina Vetro, Anna Tricarico, Ennio Prosperi, Lucia Anna Stivala, and Ornella Cazzalini. Epithelial-to-mesenchymal transition and nf-kb pathways are promoted by a mutant form of ddb2, unable to bind pcna, in uv-damaged human cells. BMC Cancer, May 2024. URL: https://doi.org/10.1186/s12885-024-12368-6, doi:10.1186/s12885-024-12368-6. This article has 5 citations and is from a peer-reviewed journal.
(perucca2024epithelialtomesenchymaltransitionand pages 1-2): Paola Perucca, Elisabetta Bassi, Martina Vetro, Anna Tricarico, Ennio Prosperi, Lucia Anna Stivala, and Ornella Cazzalini. Epithelial-to-mesenchymal transition and nf-kb pathways are promoted by a mutant form of ddb2, unable to bind pcna, in uv-damaged human cells. BMC Cancer, May 2024. URL: https://doi.org/10.1186/s12885-024-12368-6, doi:10.1186/s12885-024-12368-6. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 6-7): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 3-6): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 7-8): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 1-2): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(perucca2024epithelialtomesenchymaltransitionand pages 14-15): Paola Perucca, Elisabetta Bassi, Martina Vetro, Anna Tricarico, Ennio Prosperi, Lucia Anna Stivala, and Ornella Cazzalini. Epithelial-to-mesenchymal transition and nf-kb pathways are promoted by a mutant form of ddb2, unable to bind pcna, in uv-damaged human cells. BMC Cancer, May 2024. URL: https://doi.org/10.1186/s12885-024-12368-6, doi:10.1186/s12885-024-12368-6. This article has 5 citations and is from a peer-reviewed journal.