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This digital document is a journal article from DNA Repair, published by Elsevier in . The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by growth deficiency, skin and skeletal abnormalities, and a predisposition to cancer. Mutations in the RECQ4 gene, one of five human homologs of the E. coli recQ gene, have been identified in a subset of RTS patients. Cells derived from RTS patients show high levels of chromosomal instability, implicating this protein in the maintenance of genomic integrity. However, RECQ4 is the least characterized of the RecQ helicase family with regard to its molecular and catalytic properties. We have expressed the human RECQ4 protein in E. coli and purified it to near homogeneity. We show that RECQ4 has an ATPase function that is activated by DNA, with ssDNA being much more effective than dsDNA in this regard. We have determined that a DNA length of 60 nucleotides is required to maximally activate ATP hydrolysis by RECQ4, while the minimal site size for ssDNA binding by RECQ4 is between 20 and 40 nucleotides. Interestingly, RECQ4 possesses a single-strand DNA annealing activity that is inhibited by the single-strand DNA binding protein RPA. Unlike the previously characterized members of the RecQ family, RECQ4 lacks a detectable DNA helicase activity. .
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This digital document is a journal article from DNA Repair, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure. .
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This digital document is a journal article from DNA Repair, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
The phosphorylation of histone H2AX at serine 139 is one of the earliest responses of mammalian cells to ionizing radiation-induced DNA breaks. DNA breaks are also generated during the terminal stages of apoptosis when chromosomal DNA is cleaved into oligonucleosomal pieces. Apoptotic DNA fragmentation and the consequent chromatin condensation are important for efficient clearing of genomic DNA and nucleosomes and for protecting the organism from auto-immmunization and oncogenic transformation. In this study, we demonstrate that H2AX is phosphorylated during apoptotic DNA fragmentation in mouse, Chinese hamster ovary, and human cells. We have previously shown that ataxia telangiectasia mutated kinase (ATM) is primarily responsible for H2AX phosphorylation in murine cells in response to ionizing radiation. Interestingly, we find here that DNA-dependent protein kinase (DNA-PK) is solely responsible for H2AX phosphorylation during apoptosis while ATM is dispensable for the process. Moreover, the kinase activity of DNA-PKcs (catalytic subunit of DNA-PK) is specifically required for the induction of @cH2AX. We further show that DNA-PKcs is robustly activated in apoptotic cells, as evidenced by autophosphorylation at serine 2056, before it is inactivated by cleavage. In contrast, ATM is degraded well before DNA fragmentation and @cH2AX induction resulting in the predominance of DNA-PK during the later stages of apoptosis. Finally, we show that DNA-PKcs autophosphorylation and @cH2AX induction occur only in apoptotic nuclei with characteristic chromatin condensation but not in non-apoptotic nuclei from the same culture establishing the most direct link between DNA fragmentation, DNA-PKcs activation, and H2AX phosphorylation. It is well established that DNA-PK is inactivated by cleavage late in apoptosis in order to forestall DNA repair. Our results demonstrate, for the first time, that DNA-PK is actually activated in late apoptotic cells and is able to initiate an early step in the DNA-damage response, namely H2AX phosphorylation, before it is inactivated by proteolysis. .
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This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a central role in controlling the cellular response to ionizing radiation and other DNA-damaging agents. ATM is a 3056 amino acid polypeptide that is present in low abundance in the nucleus of human cells. Here, we describe the purification and characterization of ATM from the nuclear fraction of HeLa cells. Microgram quantities of highly stable, kinase-active ATM were prepared. Purified ATM was phosphorylated on serine 1981 and was active towards a variety of known ATM substrates, including p53 and the Bloom Syndrome helicase, BLM. The protein kinase activity of ATM was selectively inhibited by wortmannin, caffeine and LY294002 and was stimulated by charged biological polymers, including single-stranded M13 DNA (ssDNA), sheared double-stranded calf thymus DNA, heparin sulfate and poly ADP-ribose (PAR), raising the possibility that charged structures may contribute to regulation of ATM activity. However, chemical inhibition of the formation of poly ADP-ribose in cells had no effect on the activation of ATM-dependent pathways by ionizing radiation. Using gel filtration chromatography, we also show that purified ATM, as well as ATM in crude nuclear extracts from unirradiated and irradiated cells elutes with an estimated native molecular weight of approximately 600kDa. Moreover, dephosphorylation of serine 1981 did not affect the apparent molecular weight of ATM in irradiated extracts. Our results suggest that phosphorylation of serine 1981 alone may not directly regulate the subunit composition of ATM. .
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This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Ataxia-telangiectasia mutated (ATM) plays a key role in regulating the cellular response to ionizing radiation. Activation of ATM results in phosphorylation of many downstream targets that modulate numerous damage response pathways, most notably cell cycle checkpoints. In this review, we describe recent developments in our understanding of the mechanism of activation of ATM and its downstream signaling pathways, and explore whether DNA double-strand breaks are the sole activators of ATM and ATM-dependent signaling pathways. .
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This digital document is a journal article from DNA Repair, published by Elsevier in . The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
While the structure and composition of chromatin not only influences the type and extent of DNA damage incurred by eukaryotic cells, it also poses a major obstacle to the efficient repair of genomic lesions. Understanding how DNA repair processes occur in the context of nuclear chromatin is a current experimental challenge, especially in mammalian cells where the powerful tools of genetic analysis that have been so successful in elucidating repair mechanisms in yeast have seen only limited application. Even so, work over the last decade with both yeast and mammalian cells has provided a rather detailed description of how nucleosomes, the basic subunit of chromatin, influence both DNA damage and repair in all eukaryotic cells. The picture that has emerged is, nonetheless, incomplete since mammalian chromatin is far more complex than simply consisting of vast arrays of histone-containing nucleosome core particles. Members of the ''High Mobility Group'' (HMG) of non-histone proteins are essential, and highly dynamic, constituents of mammalian chromosomes that participate in all aspects of chromatin structure and function, including DNA repair processes. Yet comparatively little is known about how HMG proteins participate in the molecular events of DNA repair in vivo. What information is available, however, indicates that all three major families of mammalian HMG proteins (i.e., HMGA, HMGB and HMGN) participate in various DNA repair processes, albeit in different ways. For example, HMGN proteins have been shown to stimulate nucleotide excision repair (NER) of ultraviolet light (UV)-induced cyclobutane pyrimidine dimer (CPD) lesions of DNA in vivo. In contrast, HMGA proteins have been demonstrated to preferentially bind to, and inhibit NER of, UV-induced CPDs in stretches of AT-rich DNA both in vitro and in vivo. HMGB proteins, on the other hand, have been shown to both selectively bind to, and inhibit NER of, cisplatin-induced DNA intrastrand cross-links and to bind to misincorporated nucleoside analogs and, depending on the biological circumstances, either promote lesion repair or induce cellular apoptosis. Importantly, from a medical perspective, the ability of the HMGA and HMGB proteins to inhibit DNA repair in vivo suggests that they may be intimately involved with the accumulation of genetic mutations and chromosome instabilities frequently observed in cancers. Not surprisingly, therefore, the HMG proteins are being actively investigated as potential new therapeutic drug targets for the treatment of cancers and other diseases. .
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Karl Frankton is a pathologist with a CDC field team in Somalia. For two days, they have tried to isolate a virus that has wiped out a village on the Wabi Shebelle River. There are no clues, only 84 suffocated human beings. It is July 30, 2011 and Karl Frankton is about to enter an ecological nightmare more deadly than anything imaginable. Since retiring from senior positions in the pharmaceutical, chemical, and entertainment industries, Gary Naiman has focused on stories that carry a harsh warning--If you love high adventure, touchable characters, and a mind-gripping story, please enjoy PPM. . . . 8.5 hours - Read By Gregory Papst.
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