共查询到11条相似文献,搜索用时 0 毫秒
1.
In mammalian cells, a conserved multiprotein complex of Mre11, Rad50 and NBS1 (also known as nibrin and p95) is important for double-strand break repair, meiotic recombination and telomere maintenance. This complex forms nuclear foci and may be a sensor of double-strand breaks. In the absence of the early region E4, the double-stranded DNA genome of adenovirus is joined into concatemers too large to be packaged. We have investigated the cellular proteins involved in this concatemer formation and how they are inactivated by E4 products during a wild-type infection. Here we show that concatemerization requires functional Mre11 and NBS1, and that these proteins are found at foci adjacent to viral replication centres. Infection with wild-type virus results in both reorganization and degradation of members of the Mre11-Rad50-NBS1 complex. These activities are mediated by three viral oncoproteins that prevent concatemerization. This targeting of cellular proteins involved in genomic stability suggests a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins. 相似文献
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The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair 总被引:17,自引:0,他引:17
Hopfner KP Craig L Moncalian G Zinkel RA Usui T Owen BA Karcher A Henderson B Bodmer JL McMurray CT Carney JP Petrini JH Tainer JA 《Nature》2002,418(6897):562-566
The Mre11 complex (Mre11 Rad50 Nbs1) is central to chromosomal maintenance and functions in homologous recombination, telomere maintenance and sister chromatid association. These functions all imply that the linked binding of two DNA substrates occurs, although the molecular basis for this process remains unknown. Here we present a 2.2 A crystal structure of the Rad50 coiled-coil region that reveals an unexpected dimer interface at the apex of the coiled coils in which pairs of conserved Cys-X-X-Cys motifs form interlocking hooks that bind one Zn(2+) ion. Biochemical, X-ray and electron microscopy data indicate that these hooks can join oppositely protruding Rad50 coiled-coil domains to form a flexible bridge of up to 1,200 A. This suggests a function for the long insertion in the Rad50 ABC-ATPase domain. The Rad50 hook is functional, because mutations in this motif confer radiation sensitivity in yeast and disrupt binding at the distant Mre11 nuclease interface. These data support an architectural role for the Rad50 coiled coils in forming metal-mediated bridging complexes between two DNA-binding heads. The resulting assemblies have appropriate lengths and conformational properties to link sister chromatids in homologous recombination and DNA ends in non-homologous end-joining. 相似文献
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Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint 总被引:51,自引:0,他引:51
The checkpoint kinase proteins Mec1 and Rad53 are required in the budding yeast, Saccharomyces cerevisiae, to maintain cell viability in the presence of drugs causing damage to DNA or arrest of DNA replication forks. It is thought that they act by inhibiting cell cycle progression, allowing time for DNA repair to take place. Mec1 and Rad53 also slow S phase progression in response to DNA alkylation, although the mechanism for this and its relative importance in protecting cells from DNA damage have not been determined. Here we show that the DNA-alkylating agent methyl methanesulphonate (MMS) profoundly reduces the rate of DNA replication fork progression; however, this moderation does not require Rad53 or Mec1. The accelerated S phase in checkpoint mutants, therefore, is primarily a consequence of inappropriate initiation events. Wild-type cells ultimately complete DNA replication in the presence of MMS. In contrast, replication forks in checkpoint mutants collapse irreversibly at high rates. Moreover, the cytotoxicity of MMS in checkpoint mutants occurs specifically when cells are allowed to enter S phase with DNA damage. Thus, preventing damage-induced DNA replication fork catastrophe seems to be a primary mechanism by which checkpoints preserve viability in the face of DNA alkylation. 相似文献
4.
A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage 总被引:11,自引:0,他引:11
Woudstra EC Gilbert C Fellows J Jansen L Brouwer J Erdjument-Bromage H Tempst P Svejstrup JQ 《Nature》2002,415(6874):929-933
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用计算机对人类TSPYl基因P53结合位点的鉴定 总被引:2,自引:0,他引:2
根据p53下游基因在其调节区域(启动子或内含子)含有与P53蛋白特异性结合的一致性序列5’-RRRCWWGYYYN(0-13)RRRCWWGYYY-3’,R—G或A,W—T或A,Y—C或T,N—A,C,T,G。用计算机对人类基因组中P53结合位点进行了研究,发现Y染色体上的TSPY1基因内含子中含有这样的一致性序列5’-GGGCTAGTTTtgGAGCTAGCCT-3’,意味着TSPY1基因有可能是一个p53下游基因。 相似文献
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用计算机对人类TSPY1基因P53结合位点的鉴定 总被引:1,自引:0,他引:1
根据p53下游基因在其调节区域(启动子或内含子)含有与P53蛋白特异性结合的一致性序列5’ –RRRCWWGYYYN(013) RRRCWWGYYY3’,R=G或A,W=T或A,Y=C或T,N=A,C,T,G。用计算机对人类基因组中P53结合位点进行了研究,发现Y染色体上的TSPY1基因内含子中含有这样的一致性序列5’GGGCTAGTTTtgGAGCTAGCCT3’,意味着TSPY1基因有可能是一个p53下游基因。 相似文献
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Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma 总被引:1,自引:0,他引:1
Varela I Tarpey P Raine K Huang D Ong CK Stephens P Davies H Jones D Lin ML Teague J Bignell G Butler A Cho J Dalgliesh GL Galappaththige D Greenman C Hardy C Jia M Latimer C Lau KW Marshall J McLaren S Menzies A Mudie L Stebbings L Largaespada DA Wessels LF Richard S Kahnoski RJ Anema J Tuveson DA Perez-Mancera PA Mustonen V Fischer A Adams DJ Rust A Chan-on W Subimerb C Dykema K Furge K Campbell PJ Teh BT Stratton MR Futreal PA 《Nature》2011,469(7331):539-542
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NIE Jing LIU Lin ZHAO XiaoHang XIE Ping ZHOU PingKun XING GuiChun LIU XiangJun HE FuChu HAN WeiDong * & ZHANG LingQiang * Department of Molecular Biology General Hospital of Chinese People’s Liberation Army Beijing China State Key Laboratory of Proteomics Beijing Proteome Research Center Beijing Institute of Radiation Medicine Beijing Department of General Surgery Chi... 《科学通报(英文版)》2011,(30)
The tumor suppressor p53 locates at the key point of cell growth or apoptosis balance, and the expression level of p53 is tightly controlled by ubiquitin ligases including MDM2. Upon DNA damage stresses, p53 was accumulated and activated, leading to cell cycle arrest or apoptosis. We previously showed that Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53. However, it is uncle... 相似文献
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Jing Nie Lin Liu XiaoHang Zhao Ping Xie PingKun Zhou GuiChun Xing XiangJun Liu FuChu He WeiDong Han LingQiang Zhang 《科学通报(英文版)》2011,56(30):3155-3161
The tumor suppressor p53 locates at the key point of cell growth or apoptosis balance, and the expression level of p53 is
tightly controlled by ubiquitin ligases including MDM2. Upon DNA damage stresses, p53 was accumulated and activated, leading
to cell cycle arrest or apoptosis. We previously showed that Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes
p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53.
However, it is unclear how the Smurf1-MDM2 interaction is regulated in response to DNA damage stress. Here, we show that in
response to etoposide treatment Smurf1 dissociates from MDM2, resulting in MDM2 destabilization and p53 accumulation. The
negative regulation of Smurf1 on apoptosis is released. Notably, this dissociation is a slow process rather than a rapid response,
implicating high expression of Smurf1 might confer the resistance against p53 activation. Consistent with this notion, we
observed that Smurf1/2 ligases are highly expressed in colon cancer, esophageal squamous cell carcinoma and pancreatic cancer
tissues, suggesting the oncogenic tendency of Smurf1/2. 相似文献