共查询到20条相似文献,搜索用时 31 毫秒
1.
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
2.
The ataxia-telangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage. 相似文献
3.
SIRT6 promotes DNA repair under stress by activating PARP1 总被引:2,自引:0,他引:2
Mao Z Hine C Tian X Van Meter M Au M Vaidya A Seluanov A Gorbunova V 《Science (New York, N.Y.)》2011,332(6036):1443-1446
Sirtuin 6 (SIRT6) is a mammalian homolog of the yeast Sir2 deacetylase. Mice deficient for SIRT6 exhibit genome instability. Here, we show that in mammalian cells subjected to oxidative stress SIRT6 is recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination. Our results indicate that SIRT6 physically associates with poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly-ADP-ribosylase activity and enhancing DSB repair under oxidative stress. 相似文献
4.
Dornan D Shimizu H Mah A Dudhela T Eby M O'rourke K Seshagiri S Dixit VM 《Science (New York, N.Y.)》2006,313(5790):1122-1126
The ataxia telangiectasia mutated (ATM) protein kinase is a critical component of a DNA-damage response network configured to maintain genomic integrity. The abundance of an essential downstream effecter of this pathway, the tumor suppressor protein p53, is tightly regulated by controlled degradation through COP1 and other E3 ubiquitin ligases, such as MDM2 and Pirh2; however, the signal transduction pathway that regulates the COP1-p53 axis following DNA damage remains enigmatic. We observed that in response to DNA damage, ATM phosphorylated COP1 on Ser(387) and stimulated a rapid autodegradation mechanism. Ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm, and ATM-dependent phosphorylation of COP1 on Ser(387) was both necessary and sufficient to disrupt the COP1-p53 complex and subsequently to abrogate the ubiquitination and degradation of p53. Furthermore, phosphorylation of COP1 on Ser(387) was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage. 相似文献
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An oncogene-induced DNA damage model for cancer development 总被引:6,自引:0,他引:6
Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations. 相似文献
7.
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
8.
Faithful chromosome segregation and repair of DNA double-strand breaks (DSBs) require cohesin, the protein complex that mediates sister-chromatid cohesion. Cohesion between sister chromatids is thought to be generated only during ongoing DNA replication by an obligate coupling between cohesion establishment factors such as Eco1 (Ctf7) and the replisome. Using budding yeast, we challenge this model by showing that cohesion is generated by an Eco1-dependent but replication-independent mechanism in response to DSBs in G(2)/M. Furthermore, our studies reveal that Eco1 has two functions: a cohesive activity and a conserved acetyltransferase activity, which triggers the generation of cohesion in response to the DSB and the DNA damage checkpoint. Finally, the DSB-induced cohesion is not limited to broken chromosomes but occurs also on unbroken chromosomes, suggesting that the DNA damage checkpoint through Eco1 provides genome-wide protection of chromosome integrity. 相似文献
9.
Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses 总被引:1,自引:0,他引:1
Anastasiou D Poulogiannis G Asara JM Boxer MB Jiang JK Shen M Bellinger G Sasaki AT Locasale JW Auld DS Thomas CJ Vander Heiden MG Cantley LC 《Science (New York, N.Y.)》2011,334(6060):1278-1283
Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys(358). This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys(358) to Ser(358) oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress. 相似文献
10.
Ström L Karlsson C Lindroos HB Wedahl S Katou Y Shirahige K Sjögren C 《Science (New York, N.Y.)》2007,317(5835):242-245
Sister-chromatid cohesion, established during replication by the protein complex cohesin, is essential for both chromosome segregation and double-strand break (DSB) repair. Normally, cohesion formation is strictly limited to the S phase of the cell cycle, but DSBs can trigger cohesion also after DNA replication has been completed. The function of this damage-induced cohesion remains unknown. In this investigation, we show that damage-induced cohesion is essential for repair in postreplicative cells in yeast. Furthermore, it is established genome-wide after induction of a single DSB, and it is controlled by the DNA damage response and cohesin-regulating factors. We thus define a cohesion establishment pathway that is independent of DNA duplication and acts together with cohesion formed during replication in sister chromatid-based DSB repair. 相似文献
11.
DNA双链断裂(DSBs)是细胞最严重的损伤形式之一。高等动植物中主要通过非同源末端连接(NHEJ)途径进行DNA双链断裂修复。该途径不依赖DNA同源性,由一些修复因子如:Ku蛋白异二聚体、DNA-PKcs 、XRCC4、ligaseⅣ等,将断裂末端直接连接进行修复。综述了植物DNA双链断裂损伤修复的主要途径及其相关基因研究的进展,探讨了植物DNA损伤修复研究中存在的问题与发展方向。 相似文献
12.
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage 总被引:5,自引:0,他引:5
Matsuoka S Ballif BA Smogorzewska A McDonald ER Hurov KE Luo J Bakalarski CE Zhao Z Solimini N Lerenthal Y Shiloh Y Gygi SP Elledge SJ 《Science (New York, N.Y.)》2007,316(5828):1160-1166
Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals. 相似文献
13.
Weller GR Kysela B Roy R Tonkin LM Scanlan E Della M Devine SK Day JP Wilkinson A d'Adda di Fagagna F Devine KM Bowater RP Jeggo PA Jackson SP Doherty AJ 《Science (New York, N.Y.)》2002,297(5587):1686-1689
In eukaryotic cells, double-strand breaks (DSBs) in DNA are generally repaired by the pathway of homologous recombination or by DNA nonhomologous end joining (NHEJ). Both pathways have been highly conserved throughout eukaryotic evolution, but no equivalent NHEJ system has been identified in prokaryotes. The NHEJ pathway requires a DNA end-binding component called Ku. We have identified bacterial Ku homologs and show that these proteins retain the biochemical characteristics of the eukaryotic Ku heterodimer. Furthermore, we show that bacterial Ku specifically recruits DNA ligase to DNA ends and stimulates DNA ligation. Loss of these proteins leads to hypersensitivity to ionizing radiation in Bacillus subtilis. These data provide evidence that many bacteria possess a DNA DSB repair apparatus that shares many features with the NHEJ system of eukarya and suggest that this DNA repair pathway arose before the prokaryotic and eukaryotic lineages diverged. 相似文献
14.
[目的]研究电刺激处理对宰后成熟过程中牛肉蛋白质的影响。[方法]利用牛背最长肌双向电泳凝胶体系研究电刺激后牛背最长肌中的差异蛋白质,分析宰后1和3 d时电刺激处理牛背最长肌中有显著降解的差异蛋白点。[结果]与未电刺激样品相比,在宰后1和3 d电刺激处理牛背最长肌中有12个蛋白点表达明显下调,分为9种蛋白质:肌间线蛋白、肌钙蛋白-T、肌球蛋白结合蛋白H;肌酸激酶、磷酸丙糖异构酶;过氧化物氧化还原酶、磷脂酰乙醇胺结合蛋白;组蛋白、甲基转移酶。[结论]电刺激后9种蛋白质通过4条途径影响电刺激后嫩度变化,包括糖酵解代谢途径、钙激活中性蛋白酶途径、溶酶体途径和氧化应激途径。电刺激通过通过4条途径影响嫩度的信号通路表明,牛肉嫩化与氧化、凋亡有密切联系;电刺激在一定程度上抑制增殖,加速氧化和凋亡,加快嫩化。 相似文献
15.
牛肉品质的好坏,最重要的指标是嫩度。介绍了牛肉成熟机制研究进展,包括在牛肉成熟过程中嫩度的影响因素和加快牛肉成熟的技术,讨论了电刺激影响嫩度的分子机理,主要通过糖酵解代谢途径、钙激活中性蛋白酶途径、溶酶体途径、氧化应激途径影响嫩度。电刺激影响牛肉成熟过程中嫩度的信号通路表明,牛肉的嫩度与氧化和凋亡有密不可分的联系。 相似文献
16.
Aten JA Stap J Krawczyk PM van Oven CH Hoebe RA Essers J Kanaar R 《Science (New York, N.Y.)》2004,303(5654):92-95
Interactions between ends from different DNA double-strand breaks (DSBs) can produce tumorigenic chromosome translocations. Two theories for the juxta-position of DSBs in translocations, the static "contact-first" and the dynamic "breakage-first" theory, differ fundamentally in their requirement for DSB mobility. To determine whether or not DSB-containing chromosome domains are mobile and can interact, we introduced linear tracks of DSBs in nuclei. We observed changes in track morphology within minutes after DSB induction, indicating movement of the domains. In a subpopulation of cells, the domains clustered. Juxtaposition of different DSB-containing chromosome domains through clustering, which was most extensive in G1 phase cells, suggests an adhesion process in which we implicate the Mre11 complex. Our results support the breakage-first theory to explain the origin of chromosomal translocations. 相似文献
17.
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
18.
Lorenz A Osman F Sun W Nandi S Steinacher R Whitby MC 《Science (New York, N.Y.)》2012,336(6088):1585-1588
The formation of healthy gametes depends on programmed DNA double-strand breaks (DSBs), which are each repaired as a crossover (CO) or non-crossover (NCO) from a homologous template. Although most of these DSBs are repaired without giving COs, little is known about the genetic requirements of NCO-specific recombination. We show that Fml1, the Fanconi anemia complementation group M (FANCM)-ortholog of Schizosaccharomyces pombe, directs the formation of NCOs during meiosis in competition with the Mus81-dependent pro-CO pathway. We also define the Rad51/Dmc1-mediator Swi5-Sfr1 as a major determinant in biasing the recombination process in favor of Mus81, to ensure the appropriate amount of COs to guide meiotic chromosome segregation. The conservation of these proteins from yeast to humans suggests that this interplay may be a general feature of meiotic recombination. 相似文献
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RA Periana DJ Taube S Gamble H Taube T Satoh H Fujii 《Science (New York, N.Y.)》1998,280(5363):560-564
Platinum catalysts are reported for the direct, low-temperature, oxidative conversion of methane to a methanol derivative at greater than 70 percent one-pass yield based on methane. The catalysts are platinum complexes derived from the bidiazine ligand family that are stable, active, and selective for the oxidation of a carbon-hydrogen bond of methane to produce methyl esters. Mechanistic studies show that platinum(II) is the most active oxidation state of platinum for reaction with methane, and are consistent with reaction proceeding through carbon-hydrogen bond activation of methane to generate a platinum-methyl intermediate that is oxidized to generate the methyl ester product. 相似文献