共查询到20条相似文献,搜索用时 15 毫秒
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Functions of the MDM2 oncoprotein 总被引:34,自引:1,他引:33
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The p53 protein was discovered 20 years ago, as a cellular protein tightly bound to the large T oncoprotein of the SV40 DNA
tumour virus. Since then, research on p53 has developed in many exciting and sometimes unexpected directions. p53 is now known
to be the product of a major tumour suppressor gene that is the most common target for genetic alterations in human cancer.
The nonmutated wild-type p53 protein (wtp53) is often found within cells in a latent state and is activated in response to
various intracellular and extracellular signals. Activation involves an increase in overall p53 protein levels, as well as
qualitative changes in the protein. Upon activation, wtp53 can induce a variety of cellular responses, most notable among
which are cell cycle arrest and apoptosis. To a great extent, these effects are mediated by the ability of p53 to activate
specific target genes. In addition, the p53 protein itself possesses biochemical functions which may facilitate DNA repair
as well as apoptosis. The role of p53 in normal development and particularly in carcinogenesis has been elucidated in depth
through the use of mouse model systems. The insights provided by p53 research over the years are now beginning to be utilized
towards better diagnosis, prognosis and treatment of cancer. 相似文献
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Significant interest in synthetic DNA and RNA oligonucleotides and their analogues has marked the past two decades of research in chemistry and biochemistry. This attention was largely determined by the great potential of these compounds for various therapeutic applications such as antisense, antigene and ribozyme-based agents. Modified oligonucleotides have also become powerful molecular biological and biochemical research tools that allow fast and efficient regulation of gene expression and gene functions in vitro and in vivo. These applications in turn are based on the ability of the oligonucleotides to form highly sequence-specific complexes with nucleic acid targets of interest. This review summarizes recent advances in the design, synthesis, biochemical and structural properties of various RNA analogues. These comprise 3'-modified oligonucleotide N3'-->P5' phosphoramidates, analogues with modifications at the 2'-position of nucleoside sugar rings, or combinations of the two. Among the properties of the RNA minetics reviewed here are the thermal stability of their duplexes and triplexes, hydrolytic resistance to cellular nucleases and biological activity in in vitro and in vivo systems. In addition, key structural aspects of the complexes formed by the RNA analogues, including interaction with water molecules and ions, are analyzed and presented. 相似文献
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Molecular mechanisms involved in cisplatin cytotoxicity 总被引:15,自引:1,他引:14
cis-diamminedichloroplatinum(II) or cisplatin is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin cross-links to DNA, forming intra- and interstrand adducts, which bend and unwind the duplex and attract high-mobility-group domain and other proteins. Presumably due to a shielding effect caused by these proteins, the cisplatin-modified DNA is poorly repaired. The resulting DNA damage triggers cell-cycle arrest and apoptosis. Although it is still debatable whether the clinical success of cisplatin relies primarily on its ability to trigger apoptosis, at least two distinct pathways have been proposed to contribute to cisplatin-induced apoptosis in vitro. One involves the tumour-suppressor protein p53, the other is mediated by the p53-related protein p73. Coupling cisplatin damage to apoptosis requires mismatch repair activity, and recent observations further suggest involvement of the homologous recombinatorial repair system. At present it is generally accepted that abortive attempts to repair the DNA lesions play a key role in the cytotoxicity of the drug, and loss of the mismatch repair activity is known to cause cisplatin resistance, a major problem in antineoplastic therapy. Clearly, a better understanding of the signalling networks involved in cisplatin toxicity should provide a rational basis for the development of new therapeutic strategies. 相似文献
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Ignacio Campillo-Marcos Pedro A. Lazo 《Cellular and molecular life sciences : CMLS》2018,75(13):2375-2388
DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR). This initiating kinase must be located in chromatin, and be activated independently of the type of DNA damage. We review the contribution of the Ser-Thr vaccinia-related kinase 1 (VRK1) chromatin kinase as a new player in the signaling of DNA damage responses, at chromatin and cellular levels, and its potential as a new therapeutic target in oncology. VRK1 is involved in the regulation of histone modifications, such as histone phosphorylation and acetylation, and in the formation of γH2AX, NBS1 and 53BP1 foci induced in DDR. Induction of DNA damage by chemotherapy or radiation is a mainstay of cancer treatment. Therefore, novel treatments can be targeted to proteins implicated in the regulation of DDR, rather than by directly causing DNA damage. 相似文献
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Jessica M. Stringer Amy Winship Seng H. Liew Karla Hutt 《Cellular and molecular life sciences : CMLS》2018,75(15):2777-2792
Female fertility and offspring health are critically dependent on the maintenance of an adequate supply of high-quality oocytes. Like somatic cells, oocytes are subject to a variety of different types of DNA damage arising from endogenous cellular processes and exposure to exogenous genotoxic stressors. While the repair of intentionally induced DNA double strand breaks in gametes during meiotic recombination is well characterised, less is known about the ability of oocytes to repair pathological DNA damage and the relative contribution of DNA repair to oocyte quality is not well defined. This review will discuss emerging data suggesting that oocytes are in fact capable of efficient DNA repair and that DNA repair may be an important mechanism for ensuring female fertility, as well as the transmission of high-quality genetic material to subsequent generations. 相似文献
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H. D. Lohrer 《Cellular and molecular life sciences : CMLS》1996,52(4):316-328
A proportion of the population is exposed to acute doses of ionizing radiation through medical treatment or occupational accidents, with little knowledge of the immedate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detrimental manifestations of radiation damage. Cytotoxic stress due to ionizing radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21WAF1/CIPI, preventing the entrance into S-phase; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53as together with the retinoblastoma protein (Rb), with less defined functions during the G2 phase of the cell cycle. By comparing a variety of radioresistant cell lines derived from radiosensitive ataxia talangiectasia cells with the parental cells, some essential mechanisms that allow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition from G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation. 相似文献
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Biological functions of the ING family tumor suppressors 总被引:11,自引:0,他引:11
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Alkyltransferase-like proteins (ATLs) play a role in the protection of cells from the biological effects of DNA alkylation
damage. Although ATLs share functional motifs with the DNA repair protein and cancer chemotherapy target O
6-alkylguanine-DNA alkyltransferase, they lack the reactive cysteine residue required for alkyltransferase activity, so its
mechanism for cell protection was previously unknown. Here we review recent advances in unraveling the enigmatic cellular
protection provided by ATLs against the deleterious effects of DNA alkylation damage. We discuss exciting new evidence that
ATLs aid in the repair of DNA O
6-alkylguanine lesions through a novel repair cross-talk between DNA-alkylation base damage responses and the DNA nucleotide
excision repair pathway. 相似文献
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Endonuclease V: an unusual enzyme for repair of DNA deamination 总被引:1,自引:1,他引:0
Weiguo Cao 《Cellular and molecular life sciences : CMLS》2013,70(17):3145-3156
Endonuclease V (endo V) was first discovered as the fifth endonuclease in Escherichia coli in 1977 and later rediscovered as a deoxyinosine 3′ endonuclease. Decades of biochemical and genetic investigations have accumulated rich information on its role as a DNA repair enzyme for the removal of deaminated bases. Structural and biochemical analyses have offered invaluable insights on its recognition capacity, catalytic mechanism, and multitude of enzymatic activities. The roles of endo V in genome maintenance have been validated in both prokaryotic and eukaryotic organisms. The ubiquitous nature of endo V in the three domains of life: Bacteria, Archaea, and Eukaryotes, indicates its existence in the early evolutionary stage of cellular life. The application of endo V in mutation detection and DNA manipulation underscores its value beyond cellular DNA repair. This review is intended to provide a comprehensive account of the historic aspects, biochemical, structural biological, genetic and biotechnological studies of this unusual DNA repair enzyme. 相似文献
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Poly-ADP-ribosylation in health and disease 总被引:6,自引:0,他引:6
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U Hagen 《Experientia》1989,45(1):7-12
In order to analyze the mechanisms of biological radiation effects, the events after radiation energy absorption in irradiated organisms have to be studied by physico-chemical and biochemical methods. The radiation effects in vitro on biomolecules, especially DNA, are described, as well as their alterations in irradiated cells. Whereas in vitro, in aqueous solution, predominantly OH radicals are effective and lead to damage in single moieties of the DNA, in vivo the direct absorption of radiation energy leads to 'locally multiply-damaged sites', which produce DNA double-strand breaks and locally denatured regions. DNA damage will be repaired in irradiated cells. Error free repair leads to the original nucleotide sequence in the genome by excision or by recombination. "Error prone repair"(mutagenic repair), leads to mutation. However, the biochemistry of these processes, regulated by a number of genes, is poorly understood. In addition, more complex reactions, such as gene amplification and transposition of mobile gene elements, are responsible for mutation or malignant transformation. 相似文献
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In vitro reconstitution of homologous recombination reactions 总被引:3,自引:0,他引:3
S. C. Kowalczykowski 《Cellular and molecular life sciences : CMLS》1994,50(3):204-215
The proteins essential to homologous recombination inE. coli have been purified and their individual activities have been identified, permitting biochemical reconstitution of steps that comprise the cellular recombination process. This review focuses on the biochemical events responsible for the initiation and homologous pairing steps of genetic recombination. The properties of an in vitro recombination reaction that requires the concerted action of recA, recBCD, and SSB proteins and that is stimulated by the recombination hotspot, Chi(), are described. The recBCD enzyme serves as the initiator of this reaction; its DNA helicase activity produces single-stranded DNA that is used by the recA protein to promote homologous pairing and DNA strand invasion of supercoiled (recipient) DNA. The SSB protein acts to trap the single-stranded DNA produced by recBCD enzyme and to facilitate pairing by the recA protein. The regulatory sequence acts incis by attenuating the nuclease, but not the helicase, activity of recBCD enzyme. This attenuation assures the preservation of ssDNA produced by the DNA helicase activity and is responsible for the simulation in vitro and, presumably, in vivo. The attenuation of nuclease activity by results in the loss or functional inactivation of the recD subunit. 相似文献