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排序方式: 共有109条查询结果,搜索用时 15 毫秒
31.
Jennifer Yamtich Joann B. Sweasy 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(5):1136-1150
The X family of DNA polymerases in eukaryotic cells consists of terminal transferase and DNA polymerases β, λ, and μ. These enzymes have similar structural portraits, yet different biochemical properties, especially in their interactions with DNA. None of these enzymes possesses a proofreading subdomain, and their intrinsic fidelity of DNA synthesis is much lower than that of a polymerase that functions in cellular DNA replication. In this review, we discuss the similarities and differences of three members of Family X: polymerases β, λ, and μ. We focus on biochemical mechanisms, structural variation, fidelity and lesion bypass mechanisms, and cellular roles. Remarkably, although these enzymes have similar three-dimensional structures, their biochemical properties and cellular functions differ in important ways that impact cellular function. 相似文献
32.
Brian E. Eckenroth Jamie B. Towle-Weicksel Joann B. Sweasy Sylvie Doublié 《The Journal of biological chemistry》2013,288(48):34850-34860
DNA polymerase β (pol β) is responsible for gap filling synthesis during repair of damaged DNA as part of the base excision repair pathway. Human pol β mutations were recently identified in a high percentage (∼30%) of tumors. Characterization of specific cancer variants is particularly useful to further the understanding of the general mechanism of pol β while providing context to disease contribution. We showed that expression of the carcinoma variant E295K induces cellular transformation. The poor polymerase activity exhibited by the variant was hypothesized to be caused by the destabilization of proper active site assembly by the glutamate to lysine mutation. Here, we show that this variant exhibits an unusual preference for binding dCTP opposite a templating adenine over the cognate dTTP. Biochemical studies indicate that the noncognate competes with the cognate nucleotide for binding to the polymerase active site with the noncognate incorporation a function of higher affinity and not increased activity. In the crystal structure of the variant bound to dA:dCTP, the fingers domain closes around the mismatched base pair. Nucleotide incorporation is hindered because key residues in the polymerase active site are not properly positioned for nucleotidyl transfer. In contrast to the noncognate dCTP, neither the cognate dTTP nor its nonhydrolyzable analog induced fingers closure, as isomorphous difference Fourier maps show that the cognate nucleotides are bound to the open state of the polymerase. Comparison with published structures provides insight into the structural rearrangements within pol β that occur during the process of nucleotide discrimination. 相似文献
33.
Sreerupa Ray Miriam Rose Menezes Alireza Senejani Joann B. Sweasy 《The Yale journal of biology and medicine》2013,86(4):463-469
Since its discovery and purification in 1971, DNA polymerase ß (Pol ß) is one of
the most well-studied DNA polymerases. Pol ß is a key enzyme in the base
excision repair (BER) pathway that functions in gap filling DNA synthesis
subsequent to the excision of damaged DNA bases. A major focus of our studies is
on the cellular roles of Pol ß. We have shown that germline and tumor-associated
variants of Pol ß catalyze aberrant BER that leads to genomic instability and
cellular transformation. Our studies suggest that Pol ß is critical for the
maintenance of genomic stability and that it is a tumor suppressor. We have also
shown that Pol ß functions during Prophase I of meiosis. Pol ß localizes to the
synaptonemal complex and is critical for removal of the Spo11 complex from the
5’ ends of double-strand breaks. Studies with Pol ß mutant mice are currently
being undertaken to more clearly understand the function of Pol ß during
meiosis. In this review, we will highlight our contributions from our studies of
Pol ß germline and cancer-associated variants. 相似文献
34.
The fidelity of chromosomal segregation during cell division is important to maintain chromosomal stability in order to prevent cancer and birth defects. Although several spindle-associated molecular motors have been shown to be essential for cell division, only a few chromosome arm-associated motors have been described. Here, we investigated the role of Kinesin 5b (Kif5b) during female mouse meiotic cell development and mitotic cell division. RNA interference (RNAi)-mediated silencing of Kif5b in mouse oocytes induced significant delay in germinal vesicle breakdown (GVBD) and failure in extrusion of the first polar body (PBE). In mitotic cells, knockdown of Kif5b leads to centrosome amplification and a chromosomal segregation defect. These data suggest that KIF5B is critical in suppressing chromosomal instability at the early stages of female meiotic cell development and mitotic cell division. 相似文献
35.
The E295K DNA polymerase beta gastric cancer-associated variant interferes with base excision repair and induces cellular transformation 总被引:2,自引:0,他引:2 下载免费PDF全文
Approximately 30% of human tumors examined for mutations in polymerase beta (pol beta) appear to express pol beta variant proteins (D. Starcevic, S. Dalal, and J. B. Sweasy, Cell Cycle 3:998-1001, 2004). Many of these variants result from a single amino acid substitution. We have previously shown that the K289M and I260M colon and prostate cancer variants, respectively, induce cellular transformation most likely due to sequence-specific mutator activity (S. Dalal et al., Biochemistry 44:15664-15673, 2005; T. Lang et al., Proc. Natl. Acad. Sci. USA 101:6074-6079, 2004; J. B. Sweasy et al., Proc. Natl. Acad. Sci. USA 102:14350-14355, 2005). In the work described here, we show that the E295K gastric carcinoma pol beta variant acts in a dominant-negative manner by interfering with base excision repair. This leads to an increase in sister chromatid exchanges. Expression of the E295K variant also induces cellular transformation. Our data suggest that unfilled gaps are channeled into a homology-directed repair pathway that could lead to genomic instability. The results indicate that base excision repair is critical for maintaining genome stability and could therefore be a tumor suppressor mechanism. 相似文献
36.
Several germline single nucleotide polymorphisms (SNPs) have been identified in the POLB gene, but little is known about their cellular and biochemical impact. DNA Polymerase β (Pol β), encoded by the POLB gene, is the main gap-filling polymerase involved in base excision repair (BER), a pathway that protects the genome from the consequences of oxidative DNA damage. In this study we tested the hypothesis that expression of the POLB germline coding SNP (rs3136797) in mammalian cells could induce a cancerous phenotype. Expression of this SNP in both human and mouse cells induced double-strand breaks, chromosomal aberrations, and cellular transformation. Following treatment with an alkylating agent, cells expressing this coding SNP accumulated BER intermediate substrates, including single-strand and double-strand breaks. The rs3136797 SNP encodes the P242R variant Pol β protein and biochemical analysis showed that P242R protein had a slower catalytic rate than WT, although P242R binds DNA similarly to WT. Our results suggest that people who carry the rs3136797 germline SNP may be at an increased risk for cancer susceptibility. 相似文献
37.
Y Deng J Zhao D Sakurai KM Kaufman JC Edberg RP Kimberly DL Kamen GS Gilkeson CO Jacob RH Scofield CD Langefeld JA Kelly ME Alarcón-Riquelme BIOLUPUS GENLES Networks JB Harley TJ Vyse BI Freedman PM Gaffney KM Sivils JA James TB Niewold RM Cantor W Chen BH Hahn EE Brown PROFILE BP Tsao 《Arthritis research & therapy》2012,14(Z3):A5
38.
39.
Vidushi S Patel Steven JB Cooper Janine E Deakin Bob Fulton Tina Graves Wesley C Warren Richard K Wilson Jennifer AM Graves 《BMC biology》2008,6(1):34
Background
Vertebrate alpha (α)- and beta (β)-globin gene families exemplify the way in which genomes evolve to produce functional complexity. From tandem duplication of a single globin locus, the α- and β-globin clusters expanded, and then were separated onto different chromosomes. The previous finding of a fossil β-globin gene (ω) in the marsupial α-cluster, however, suggested that duplication of the α-β cluster onto two chromosomes, followed by lineage-specific gene loss and duplication, produced paralogous α- and β-globin clusters in birds and mammals. Here we analyse genomic data from an egg-laying monotreme mammal, the platypus (Ornithorhynchus anatinus), to explore haemoglobin evolution at the stem of the mammalian radiation. 相似文献40.
Hierarchical analysis of variation in the mitochondrial 16S rRNA gene among Hymenoptera 总被引:5,自引:2,他引:3
Nucleotide sequences from a 434-bp region of the 16S rRNA gene were
analyzed for 65 taxa of Hymenoptera (ants, bees, wasps, parasitoid wasps,
sawflies) to examine the patterns of variation within the gene fragment and
the taxonomic levels for which it shows maximum utility in phylogeny
estimation. A hierarchical approach was adopted in the study through
comparison of levels of sequence variation among taxa at different
taxonomic levels. As previously reported for many holometabolous insects,
the 16S data reported here for Hymenoptera are highly AT-rich and exhibit
strong site-to-site variation in substitution rate. More precise estimates
of the shape parameter (alpha) of the gamma distribution and the proportion
of invariant sites were obtained in this study by employing a reference
phylogeny and utilizing maximum-likelihood estimation. The effectiveness of
this approach to recovering expected phylogenies of selected hymenopteran
taxa has been tested against the use of maximum parsimony. This study finds
that the 16S gene is most informative for phylogenetic analysis at two
different levels: among closely related species or populations, and among
tribes, subfamilies, and families. Maximization of the phylogenetic signal
extracted from the 16S gene at higher taxonomic levels may require
consideration of the base composition bias and the site-to-site rate
variation in a maximum-likelihood framework.
相似文献