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The enzyme uracil DNA glycosylase (UNG) excises unwanted uracil bases in the genome using an extrahelical base recognition mechanism. Efficient removal of uracil is essential for prevention of C-to-T transition mutations arising from cytosine deamination, cytotoxic U*A pairs arising from incorporation of dUTP in DNA, and for increasing immunoglobulin gene diversity during the acquired immune response. A central event in all of these UNG-mediated processes is the singling out of rare U*A or U*G base pairs in a background of approximately 10(9) T*A or C*G base pairs in the human genome. Here we establish for the human and Escherichia coli enzymes that discrimination of thymine and uracil is initiated by thermally induced opening of T*A and U*A base pairs and not by active participation of the enzyme. Thus, base-pair dynamics has a critical role in the genome-wide search for uracil, and may be involved in initial damage recognition by other DNA repair glycosylases. 相似文献
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Some Pacific island societies, such as those of Easter Island and Mangareva, inadvertently contributed to their own collapse by causing massive deforestation. Others retained forest cover and survived. How can those fateful differences be explained? Although the answers undoubtedly involve both different cultural responses of peoples and different susceptibilities of environments, how can one determine which environmental factors predispose towards deforestation and which towards replacement of native trees with useful introduced tree species? Here we code European-contact conditions and nine environmental variables for 81 sites on 69 Pacific islands from Yap in the west to Easter in the east, and from Hawaii in the north to New Zealand in the south. We thereby detect statistical decreases in deforestation and/or forest replacement with island rainfall, elevation, area, volcanic ash fallout, Asian dust transport and makatea terrain (uplifted reef), and increases with latitude, age and isolation. Comparative analyses of deforestation therefore lend themselves to much more detailed interpretations than previously possible. These results might be relevant to similar deforestation-associated collapses (for example, Fertile Crescent, Maya and Anasazi) or the lack thereof (Japan and highland New Guinea) elsewhere in the world. 相似文献
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Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology 总被引:22,自引:0,他引:22
Fernandez-Valle C Tang Y Ricard J Rodenas-Ruano A Taylor A Hackler E Biggerstaff J Iacovelli J 《Nature genetics》2002,31(4):354-362
Neurofibromatosis type 2 is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system. It is caused by mutations in the gene NF2, encoding the growth regulator schwannomin (also known as merlin). Mutations occur throughout the 17-exon gene, with most resulting in protein truncation and undetectable amounts of schwannomin protein. Pathogenic mutations that result in production of defective schwannomin include in-frame deletions of exon 2 and three independent missense mutations within this same exon. Mice with conditional deletion of exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. Here we report that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta 1 integrin and erbB2. It defines a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2. 相似文献
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Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas 总被引:1,自引:0,他引:1
Wu G Broniscer A McEachron TA Lu C Paugh BS Becksfort J Qu C Ding L Huether R Parker M Zhang J Gajjar A Dyer MA Mullighan CG Gilbertson RJ Mardis ER Wilson RK Downing JR Ellison DW Zhang J Baker SJ;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project 《Nature genetics》2012,44(3):251-253
To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration. 相似文献
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The bacterial flagellar motor is an amazing nanomachine: built from approximately 25 different proteins, it uses an electrochemical ion gradient to drive rotation at speeds of up to 300 Hz (refs 1, 2). The flagellar motor consists of a fixed, membrane-embedded, torque-generating stator and a typically bidirectional, spinning rotor that changes direction in response to chemotactic signals. Most structural analyses so far have targeted the purified rotor, and hence little is known about the stator and its interactions. Here we show, using electron cryotomography of whole cells, the in situ structure of the complete flagellar motor from the spirochaete Treponema primitia at 7 nm resolution. Twenty individual motor particles were computationally extracted from the reconstructions, aligned and then averaged. The stator assembly, revealed for the first time, possessed 16-fold symmetry and was connected directly to the rotor, C ring and a novel P-ring-like structure. The unusually large size of the motor suggested mechanisms for increasing torque and supported models wherein critical interactions occur atop the C ring, where our data suggest that both the carboxy-terminal and middle domains of FliG are found. 相似文献
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TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function 总被引:2,自引:0,他引:2
Zhou L Lopes JE Chong MM Ivanov II Min R Victora GD Shen Y Du J Rubtsov YP Rudensky AY Ziegler SF Littman DR 《Nature》2008,453(7192):236-240