共查询到20条相似文献，搜索用时 31 毫秒
1.
Chen HT Bhandoola A Difilippantonio MJ Zhu J Brown MJ Tai X Rogakou EP Brotz TM Bonner WM Ried T Nussenzweig A 《Science (New York, N.Y.)》2000,290(5498):1962-1965
Genetic disorders affecting cellular responses to DNA damage are characterized by high rates of translocations involving antigen receptor loci and increased susceptibility to lymphoid malignancies. We report that the Nijmegen breakage syndrome protein (NBS1) and histone gamma-H2AX, which associate with irradiation-induced DNA double-strand breaks (DSBs), are also found at sites of VDJ (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 and gamma-H2AX form nuclear foci that colocalize with the T cell receptor alpha locus in response to recombination activating gene (RAG) protein-mediated VDJ cleavage. Our results suggest that surveillance of T cell receptor recombination intermediates by NBS1 and gamma-H2AX may be important for preventing oncogenic translocations. 相似文献
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The complex containing the Mre11, Rad50, and Nbs1 proteins (MRN) is essential for the cellular response to DNA double-strand breaks, integrating DNA repair with the activation of checkpoint signaling through the protein kinase ATM (ataxia telangiectasia mutated). We demonstrate that MRN stimulates the kinase activity of ATM in vitro toward its substrates p53, Chk2, and histone H2AX. MRN makes multiple contacts with ATM and appears to stimulate ATM activity by facilitating the stable binding of substrates. Phosphorylation of Nbs1 is critical for MRN stimulation of ATM activity toward Chk2, but not p53. Kinase-deficient ATM inhibits wild-type ATM phosphorylation of Chk2, consistent with the dominant-negative effect of kinase-deficient ATM in vivo. 相似文献
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The cellular DNA damage response (DDR) is initiated by the rapid recruitment of repair factors to the site of DNA damage to form a multiprotein repair complex. How the repair complex senses damaged DNA and then activates the DDR is not well understood. We show that prolonged binding of DNA repair factors to chromatin can elicit the DDR in an ATM (ataxia telangiectasia mutated)- and DNAPK (DNA-dependent protein kinase)-dependent manner in the absence of DNA damage. Targeting of single repair factors to chromatin revealed a hierarchy of protein interactions within the repair complex and suggests amplification of the damage signal. We conclude that activation of the DDR does not require DNA damage and stable association of repair factors with chromatin is likely a critical step in triggering, amplifying, and maintaining the DDR signal. 相似文献
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文章探讨了牛乳骨桥蛋白(bovine Osteopontin,bOPN)是否可引起大鼠破骨细胞(Osteoclasts,OC)γ-H2AX焦点的形成的可能性。采用全骨髓培养法培养破骨细胞,用bOPN处理破骨细胞,MTT比色法测定bOPN对破骨细胞的增殖影响,应用免疫荧光试验检测细胞核内DNA双链断裂(γ-H2AX焦点)的形成。在细胞增殖实验中,bOPN 100μg.mL-1浓度组在24 h较对照组差异显著(P<0.05);100μg.mL-1浓度组在72 h较对照组差异极显著(P<0.01);在免疫荧光试验中,1、10、100和1 000μg.mL-1处理组都可以使OC形成焦点,尤其1 000μg.mL-1处理组时数量虽不多,强度却明显增加。总之bOPN可使H2AX磷酸化,进而诱导γ-H2AX焦点的形成。 相似文献
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Potentiation of bleomycin lethality by anticalmodulin drugs: a role for calmodulin in DNA repair 总被引：6，自引：0，他引：6
Treatment of exponentially growing Chinese hamster ovary cells with bleomycin causes a dose-dependent decrease in cell survival due to DNA damage. This lethal effect can be potentiated by the addition of a nonlethal dose of the anticalmodulin drug N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide ( W13 ) but not its inactive analog N-(4-aminobutyl)-2-naphthalenesulfonamide ( W12 ). By preventing the repair of damaged DNA, W13 also inhibits recovery from potentially lethal damage induced by bleomycin. These data suggest a role for calmodulin in the DNA repair pathway. 相似文献
6.
Begum NA Kinoshita K Kakazu N Muramatsu M Nagaoka H Shinkura R Biniszkiewicz D Boyer LA Jaenisch R Honjo T 《Science (New York, N.Y.)》2004,305(5687):1160-1163
Activation-induced cytidine deaminase (AID) is required for the DNA cleavage step in immunoglobulin class switch recombination (CSR). AID is proposed to deaminate cytosine to generate uracil (U) in either mRNA or DNA. In the second instance, DNA cleavage depends on uracil DNA glycosylase (UNG) for removal of U. Using phosphorylated histone gamma-H2AX focus formation as a marker of DNA cleavage, we found that the UNG inhibitor Ugi did not inhibit DNA cleavage in immunoglobulin heavy chain (IgH) locus during CSR, even though Ugi blocked UNG binding to DNA and strongly inhibited CSR. Strikingly, UNG mutants that had lost the capability of removing U rescued CSR in UNG-/- B cells. These results indicate that UNG is involved in the repair step of CSR yet by an unknown mechanism. The dispensability of U removal in the DNA cleavage step of CSR requires a reconsideration of the model of DNA deamination by AID. 相似文献
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53BP1, a mediator of the DNA damage checkpoint 总被引：2，自引：0，他引：2
53BP1 binds to the tumor suppressor protein p53 and has a potential role in DNA damage responses. We used small interfering RNA (siRNA) directed against 53BP1 in mammalian cells to demonstrate that 53BP1 is a key transducer of the DNA damage checkpoint signal. 53BP1 was required for p53 accumulation, G2-M checkpoint arrest, and the intra-S-phase checkpoint in response to ionizing radiation. 53BP1 played a partially redundant role in phosphorylation of the downstream checkpoint effector proteins Brca1 and Chk2 but was required for the formation of Brca1 foci in a hierarchical branched pathway for the recruitment of repair and signaling proteins to sites of DNA damage. 相似文献
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本文研究了咖啡固和Ｎａ２一ＥＤＴＡ后处理对不同辐照敏感性作物幼苗ＤＮＡ、ＲＮＡ含量和修复能力的影响。结果表明，随着辐照剂量的增大，大豆（对辐射敏感）和油菜（抗辐射）７天龄幼苗下胚轴内ＤＮＡ，ＲＮＡ含量随之增大，且大豆的ＤＮＡ含量比油菜高２倍多。咖啡固和Ｎａ２一ＥＤＴＡ后处理，均高于对照。放射性３Ｈ─ＴｄＲ标记６渗入法证实，种子辐照后，７日龄幼苗体内仍存在着非按期的ＤＮＡ合成，且油菜的非按期ＤＮＡ合成能力强于大豆。咖啡固、Ｎａ２─ＥＤＴＡ和二者复合作用的后处理，抑制了ＤＮＡ的非按期修复合成，加重了辐射损伤，其抑制程度，咖啡因＋Ｎ８２－ＥＤＴＡ＞咖啡固＞Ｎ８２─ＥＤＴＡ。 相似文献
9.
Xeroderma pigmentosum group E cells lack a nuclear factor that binds to damaged DNA 总被引：43，自引：0，他引：43
The disease xeroderma pigmentosum is characterized by deficient repair of damaged DNA. Fusions of cells from different patients have defined nine genetic complementation groups (A through I), implying that DNA repair in humans involves multiple gene products. In this report, an extension of the gel electrophoresis binding assay was used to identify at least one nuclear factor that (i) bound to DNA damaged by ultraviolet radiation or the antitumor drug cisplatin, but (ii) was notably absent in cells from complementation group E. Therefore, the factor appears to participate in a versatile DNA repair pathway at the stage of binding and recognition. 相似文献
10.
Damage induced by ultraviolet light or x-rays to the DNA of a eucaryotic organism, Tetrahymena pyriformis, is repaired by a process similar to the repair system present in bacteria. This repair process, which involves defect excision and subsequent resynthesis of the damaged section of DNA, occurs in the dark. Photoreactivation of damage induced by ultraviolet light is also indicated by a reduction in observed repair synthesis. An improved method for detecting repair synthesis is described. Repair synthesis is measured in parental DNA strands isolated from cultures that have undergone normal DNA replication after the repair process. 相似文献
11.
Gari K León Ortiz AM Borel V Flynn H Skehel JM Boulton SJ 《Science (New York, N.Y.)》2012,337(6091):243-245
The function of many DNA metabolism proteins depends on their ability to coordinate an iron-sulfur (Fe-S) cluster. Biogenesis of Fe-S proteins is a multistep process that takes place in mitochondria and the cytoplasm, but how it is linked to nuclear Fe-S proteins is not known. Here, we demonstrate that MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18. Cytoplasmic MMS19 also binds to multiple nuclear Fe-S proteins involved in DNA metabolism. In the absence of MMS19, a failure to transfer Fe-S clusters to target proteins is associated with Fe-S protein instability and preimplantation death of mice in which Mms19 has been knocked out. We propose that MMS19 functions as a platform to facilitate Fe-S cluster transfer to proteins critical for DNA replication and repair. 相似文献
12.
Wang B Matsuoka S Ballif BA Zhang D Smogorzewska A Gygi SP Elledge SJ 《Science (New York, N.Y.)》2007,316(5828):1194-1198
The BRCT repeats of the breast and ovarian cancer predisposition protein BRCA1 are essential for tumor suppression. Phosphopeptide affinity proteomic analysis identified a protein, Abraxas, that directly binds the BRCA1 BRCT repeats through a phospho-Ser-X-X-Phe motif. Abraxas binds BRCA1 to the mutual exclusion of BACH1 (BRCA1-associated C-terminal helicase) and CtIP (CtBP-interacting protein), forming a third type of BRCA1 complex. Abraxas recruits the ubiquitin-interacting motif (UIM)-containing protein RAP80 to BRCA1. Both Abraxas and RAP80 were required for DNA damage resistance, G(2)-M checkpoint control, and DNA repair. RAP80 was required for optimal accumulation of BRCA1 on damaged DNA (foci) in response to ionizing radiation, and the UIM domains alone were capable of foci formation. The RAP80-Abraxas complex may help recruit BRCA1 to DNA damage sites in part through recognition of ubiquitinated proteins. 相似文献
13.
Kolas NK Chapman JR Nakada S Ylanko J Chahwan R Sweeney FD Panier S Mendez M Wildenhain J Thomson TM Pelletier L Jackson SP Durocher D 《Science (New York, N.Y.)》2007,318(5856):1637-1640
Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination. 相似文献
14.
Sobhian B Shao G Lilli DR Culhane AC Moreau LA Xia B Livingston DM Greenberg RA 《Science (New York, N.Y.)》2007,316(5828):1198-1202
Mutations affecting the BRCT domains of the breast cancer-associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-gammaH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs. 相似文献
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We used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. Using a library of partially degenerate phosphopeptides, we identified tandem BRCT (BRCA1 carboxyl-terminal) domains in PTIP (Pax transactivation domain-interacting protein) and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia- and RAD3-related) in response to gamma-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (gamma-H2AX)-containing nuclear foci, a marker of DNA damage. These findings provide a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation Met1775 --> Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer. 相似文献
17.
油茶根际土壤耐酸铝微生物的筛选 总被引：1，自引：0，他引：1
为促进农业可持续发展及微生物修复受损环境提供参考依据,采用稀释倒平板法,通过油茶林根际土壤耐酸铝微生物的分离和纯化,共获得17株耐酸铝微生物,其中,H1、H7和F3菌株的耐酸铝特性较强,可以在Al 3+浓度为100mmol/L、pH 4.5的条件下良好生长,但高铝浓度对其他菌株的生长或产孢有明显的抑制作用。经初步鉴定,H1、H7和F3菌株分别属于毛霉属(Mucor sp)、青霉属(Penicillium sp)和孢囊链霉菌属(Streptosporangium sp)。 相似文献
18.
内皮祖细胞(endothelial progenitor cell,EPC)是修复损伤血管内皮的细胞库,EPC功能异常和数量减少是内皮功能障碍的主要原因,而内皮功能障碍是多种内皮损伤性疾病的始动因素。利用细胞疗法输注体外扩增的EPC来修复受损血管内皮已成为当前防治心脑血管疾病的有效手段。但单独输注EPC修复受损血管内皮的疗效不甚明显,其与血管内皮损伤后局部微环境的改变以及多种细胞因子的干预影响EPC的动员、归巢和分化有较大关系。因此探讨药物干预促进EPC对受损血管内皮的修复具有一定的科学意义,而中医药是伟大的宝库,从中选择有效的药物和方法促进EPC修复受损血管内皮具有广阔的应用前景。 相似文献
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本文通过对． Ｃ Ｏ Ｍ 程序和． Ｅ Ｘ Ｅ 程序加载时不同内存映象的研究进而得出：． Ｃ Ｏ Ｍ 程序只有一个物理段,段的最大长度为６４ Ｋ Ｂ：． Ｃ Ｏ Ｍ 程序只能从偏移地址为１００ Ｈ 处开始执行。 Ｄ Ｏ Ｓ 对． Ｅ Ｘ Ｅ 文件长度没有约束,便于组织大型应用程序;以及． Ｅ Ｘ Ｅ 文件中用 Ｅ Ｎ Ｄ 启动标号来说明启动点,用 Ｐ Ｕ Ｓ Ｈ Ｄ Ｓ 来保存程序段前缀的段地址,用 Ｓ Ｕ Ｂ Ａ Ｘ, Ａ Ｘ 和 Ｐ Ｕ Ｓ Ｈ Ａ Ｘ 指令来保存 Ｐ Ｓ Ｐ 中 Ｉ Ｎ Ｔ２０ Ｈ 指令首地址的必要性。从中还可看出：由于． Ｃ Ｏ Ｍ 程序比． Ｅ Ｘ Ｅ 程序规模小而简单,所以． Ｃ Ｏ Ｍ 程序装入速度比． Ｅ Ｘ Ｅ 程序装入速度要快。为进一步发挥汇编语言程序执行速度快的优势提供参考。 相似文献