更新于：2024-09-19

DDB2

更新于：2024-09-19

基本信息

别名

damage specific DNA binding protein 2、Damage-specific DNA-binding protein 2、DDB p48 subunit

+ [8]

简介

Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:9892649, PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899, PubMed:32789493). Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386, PubMed:14751237, PubMed:32789493). The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386). Also functions as the substrate recognition module for the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1) (PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899, PubMed:26572825). The DDB2-CUL4-ROC1 complex may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage (PubMed:16678110, PubMed:16473935). The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair (PubMed:16678110, PubMed:16473935). The DDB2-CUL4-ROC1 complex also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER (PubMed:15882621). The DDB2-CUL4-ROC1 complex also ubiquitinates KAT7/HBO1 in response to DNA damage, leading to its degradation: recognizes KAT7/HBO1 following phosphorylation by ATR (PubMed:26572825). Inhibits UV-damaged DNA repair. Inhibits UV-damaged DNA repair.

关联

100 项与 DDB2 相关的临床结果

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100 项与 DDB2 相关的转化医学

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0 项与 DDB2 相关的专利（医药）

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506

项与 DDB2 相关的文献（医药）

2024-07-22·Radiation Research

Biomarkers for Radiation Biodosimetry and Correlation with Hematopoietic Injury in a Humanized Mouse Model

Article

作者: Taveras, Maria ; Shuryak, Igor ; Phillippi, Michelle A ; Broustas, Constantinos G ; Turner, Helen C ; Bacon, Bezalel A ; Wu, Xuefeng ; Wang, Qi

After a large-scale radiological or nuclear event, hundreds of thousands of people may be exposed to ionizing radiation and require subsequent medical management. Acute exposure to moderate doses (2–6 Gy) of radiation can lead to the hematopoietic acute radiation syndrome, in which the bone marrow (BM) is severely compromised, and severe hemorrhage and infection are common. Previously, we have developed a panel of intracellular protein markers (FDXR, ACTN1, DDB2, BAX, p53 and TSPYL2), designed to reconstruct absorbed radiation dose from human peripheral blood (PB) leukocyte samples in humanized mice up to 3 days after exposure. The objective of this work was to continue to use the humanized mouse model to evaluate biomarker dose-/time- kinetics in human PB leukocytes in vivo, at an earlier (day 2) and later (day 7) time point, after exposure to total-body irradiation (TBI) doses of 0 to 2 Gy of X rays. In addition, to assess hematological sensitivity and radiation-induced injury, PB leukocyte cell counts, human BM hematopoietic stem cell (HSC) and progenitor cell [multipotent progenitor (MPP), common myeloid progenitor (CMP), granulocyte myeloid progenitor (GMP), megakaryocyte/erythrocyte progenitor (MEP) and multi-lymphoid progenitor (MLP)] levels were measured, and their correlation was also examined as the BM damages are difficult to assess by routine tests. Peripheral blood B-cells were significantly lower after TBI doses of 0.5 Gy on day 2 and 2 Gy on days 2 and 7; T-cells were significantly reduced only on day 2 after 2 Gy TBI. Bone marrow HSCs and MPP cells showed a dose-dependent depletion after irradiation with 0.5 Gy and 2 Gy on day 2, and after 1 Gy and 2 Gy on day 7. Circulating B cells correlated with HSCs, MPP and MLP cells on day 2, whereas T cells correlated with MPP, and myeloid cells correlated with MLP cells. On day 7, B cells correlated with MPP, CMP, GMP and MEP, while myeloid cells correlated with CMP, GMP and MEP. The intracellular leukocyte biomarkers were able to discriminate unirradiated and irradiated samples at different time points calculated by receiver operating characteristic (ROC) curve. Using machine learning algorithm methods, combining ACTN1, p53, TSPYL2 and PB-T cell and PB-B cell counts served as a strong predictor (area under the ROC >0.8) to distinguish unirradiated and irradiated samples independent of the days after TBI. The results further validated our biomarker-based triage assay and additionally evaluated the radiation sensitivity of the hematopoietic system after TBI exposures.

2024-06-30·The FASEB Journal

DDB2 promotes melanoma cell growth by transcriptionally regulating the expression of KMT2A and predicts a poor prognosis

Article

作者: Zhang, Chi ; Sun, Haohui ; Zhang, Changlin ; Zhong, Li ; Li, Weizhao ; Li, Tian ; Liu, Lixiang ; Huang, Jiajia ; Li, Miao

AbstractIdentification of potential key targets of melanoma, a fatal skin malignancy, is critical to the development of new cancer therapies. Lysine methyltransferase 2A (KMT2A) promotes melanoma growth by activating the human telomerase reverse transcriptase (hTERT) signaling pathway; however, the exact mechanism remains elusive. This study aimed to reveal new molecular targets that regulate KMT2A expression and melanoma growth. Using biotin–streptavidin–agarose pull‐down and proteomics, we identified Damage‐specific DNA‐binding protein 2 (DDB2) as a KMT2A promoter‐binding protein in melanoma cells and validated its role as a regulator of KMT2A/hTERT signaling. DDB2 knockdown inhibited the expression of KMT2A and hTERT and inhibited the growth of melanoma cells in vitro. Conversely, overexpression of DDB2 activated the expression of KMT2A and promoted the growth of melanoma cells. Additionally, we demonstrated that DDB2 expression was higher in tumor tissues of patients with melanoma than in corresponding normal tissues and was positively correlated with KMT2A expression. Kaplan–Meier analysis showed a poor prognosis in patients with high levels of DDB2 and KMT2A. Overall, our data suggest that DDB2 promotes melanoma cell growth through the transcriptional regulation of KMT2A expression and predicts poor prognosis. Therefore, targeting DDB2 may regulate the effects of KMT2A on melanoma growth and progression, providing a new potential therapeutic strategy for melanoma.

2024-06-01·The Journal of Obstetrics and Gynecology of India

Cancer Stem Cells (CD44+/CD24−), RAD6, DDB2 Immunohistochemistry Expression and IHC-UNEDO Scoring System As Predictor of Ovarian Cancer Chemoresistance

Article

作者: Sihombing, Unedo Hence Markus ; Widyawati, Retno ; Gandamihardja, Supriadi ; Fuady, Dzicky Rifqi ; Purwoto, Gatot ; Andrijono, Andrijono ; Kekalih, Aria ; Harahap, Alida R ; Rustamadji, Primariadewi

BackgroundsOvarian cancer is a deadly women cancer with many chemoresistance after standard treatment. Ovarian cancer tissues' CD44⁺/CD24^- (CSCs), RAD6 overexpression and DDB2 underexpression are associated with chemoresistance, recurrence, and poor prognosis of the disease because of the existence of cancer stem cells (CSCs). We tried to analyze the expression of those three proteins while building a predictor scoring system to predict the ovarian cancer chemoresistance from the ovarian cancer tissue immunohistochemistry.Materials and MethodsWe conducted a cohort study of 64 patients divided into two groups (32 patients in each group) at the Cipto Mangunkusumo, Tarakan, Dharmais, and Fatmawati Hospital which are located in Jakarta city, Indonesia. The patients underwent cytoreductive debulking and histopathological examination continued by six series of chemotherapy followed by six months of observation. We divided the groups into chemoresistant and chemosensitive by using Response Criteria in Solid Tumors (RECIST) criteria. Ovarian cancer tissue immunohistochemistry tests were then performed to count the CSCs, RAD6 and DDB2 expressions.ResultsWe found relationship between increased CSCs, RAD6 and reduced DDB2 (p < 0.05) expression in ovarian cancer tissue with the chemoresistance. A possible predictor scoring system named IHC-UNEDO scoring was built to aid the ovarian cancer chemoresistance prediction.ConclusionsThe conclusion is that CSCs, RAD6 and DDB2 expressions are significantly associated with ovarian cancer chemoresistance, and IHC-UNEDO scoring should be considered as a tool to predict ovarian cancer chemoresistance.

项与 DDB2 相关的新闻（医药）

2022-07-11

·生物谷

GPS是一种潜在的治疗糖尿病的药物，恢复胰岛素信号通路

2型糖尿病(T2 DM)是以脂糖代谢紊乱为特征的疾病，临床表现主要为胰岛素抵抗和相对胰岛素缺乏。在生理条件下，胰岛素激活肝脏胰岛素信号通路，增加肝脏糖原储备，抑制肝脏糖异生，调节脂肪合成，是维持糖脂代谢动态平衡的最重要机制。众所周知，肝脏胰岛素抵抗(Hir)是2型糖尿病和非酒精性脂肪性肝病等代谢性疾病发展的关键因素。非酒精性脂肪肝的全球流行影响着超过55%的II型糖尿病患者，而非酒精性脂肪性肝炎(NASH)在II型糖尿病患者中的患病率估计为37%。近日，来自中山大学的研究者们在Acta Pharmaceutica Sinica B杂志上发表了题为“Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism”的文章，该研究确定GPS是一种潜在的治疗糖尿病的药物，它可以抑制PAQR3的表达，并直接靶向PAQR3，恢复胰岛素信号通路。图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1016/j.apsb.2021.12.023胰岛素受体后信号传导受阻是胰岛素抵抗糖尿病的主要发病机制。孕激素和ADIPOQ受体3(PAQR3)是炎症和代谢的关键调节因子，可以负向调节PI3K/AKT信号通路。在本研究中，研究者报道了龙胆苦苷(GPS)，龙胆环烯醚萜糖苷的主要生物活性成分，在棕榈酸(PA)处理的HepG2细胞中，减少了脂质的合成，增加了葡萄糖的利用。此外，GPS改善了链脲佐菌素(STZ)治疗高脂饮食(HFD)诱导的糖尿病小鼠的糖脂代谢。本研究结果表明，GPS通过促进DNA结合蛋白2(DDB2)介导的PAQR3泛素化降解来促进PI3K/AKT轴的激活。此外，表面等离子体共振(SPR)、微量热电泳法(MST)和热位移法(TSA)的结果表明，GPS直接与PAQR3结合。分子对接和细胞热漂移分析(CETSA)结果表明，GPS直接与PAQR3 NH2末端的Leu40、Asp42、Glu69、Tyr125和Ser129等氨基酸结合，并在空间上抑制PAQR3与PI3K催化亚基(P110a)的相互作用，恢复PI3K/AKT信号通路。全球定位系统改善胰岛素抵抗机制的图解图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1016/j.apsb.2021.12.023本研究阐明了GPS改善胰岛素抵抗的一个新靶点。研究者发现GPS通过促进DDB2介导的PAQR3泛素降解来抑制PAQR3的表达。重要的是，研究者证明了GPS直接与PAQR3的末端结合，并在空间上抑制了PAQR3和P110a之间的相互作用，从而恢复了PI3K/AKT信号通路。本研究结果为应用GPS恢复糖尿病患者的胰岛素敏感性提供了理论依据。参考文献：Haiming Xiao et al. Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism. Acta Pharm Sin B. 2022 Jun;12(6):2887-2904. doi: 10.1016/j.apsb.2021.12.023.

蛋白降解靶向嵌合体