Abstract:
:Hydroxyurea (HU) has been used for the treatment of multiple diseases, such as cancer. The therapeutic effect is generally believed to be due to the suppression of ribonucleotide reductase (RNR), which slows DNA polymerase movement at replication forks and induces an S phase cell cycle arrest in proliferating cells. Although aberrant mitosis and DNA damage generated at collapsed forks are the likely causes of cell death in the mutants with defects in replication stress response, the mechanism underlying the cytotoxicity of HU in wild-type cells remains poorly understood. While screening for new fission yeast mutants that are sensitive to replication stress, we identified a novel mutation in the erg11 gene encoding the enzyme sterol-14α-demethylase in the ergosterol biosynthesis pathway that dramatically sensitizes the cells to chronic HU treatment. Surprisingly, HU mainly arrests the erg11 mutant cells in cytokinesis, not in S phase. Unlike the reversible S phase arrest in wild-type cells, the cytokinesis arrest induced by HU is relatively stable and occurs at low doses of the drug, which likely explains the remarkable sensitivity of the mutant to HU. We also show that the mutation causes sterol deficiency, which may predispose the cells to the cytokinesis arrest and lead to cell death. We hypothesize that in addition to the RNR, HU may have a secondary unknown target(s) inside cells. Identification of such a target(s) may greatly improve the chemotherapies that employ HU or help to expand the clinical usage of this drug for additional pathological conditions.
journal_name
Geneticsjournal_title
Geneticsauthors
Xu YJ,Singh A,Alter GMdoi
10.1534/genetics.116.191536subject
Has Abstractpub_date
2016-11-01 00:00:00pages
959-973issue
3eissn
0016-6731issn
1943-2631pii
genetics.116.191536journal_volume
204pub_type
杂志文章相关文献
GENETICS文献大全abstract::Vegetative incompatibility in fungi has long been known to reduce the transmission of viruses between individuals, but the barrier to transmission is incomplete. In replicated laboratory assays, we showed conclusively that the transmission of viruses between individuals of the chestnut blight fungus Cryphonectria para...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2001-09-01 00:00:00
abstract::Two alternate transcripts of the single copy Alcohol dehydrogenase (Adh) gene accumulate with developmental specificity in all of 12 species of Hawaiian picture-winged Drosophila which have been examined. Relative to the paradigm species D. affinidisjuncta, the Adh transcript normally restricted to larvae is found to ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::Predicting the chromosomal location of mapped markers has been difficult because linkage maps do not reveal differences in crossover frequencies along the physical structure of chromosomes. Here we combine a physical crossover map based on the distribution of recombination nodules (RNs) on Solanum lycopersicum (tomato...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.107.074138
更新日期:2007-08-01 00:00:00
abstract::Statistical associations between phenotypic traits often result from shared developmental processes and include both covariation between the trait values and more complex associations between higher moments of the joint distribution of traits. In this article, an analytical technique for calculating the covariance bet...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.166.1.513
更新日期:2004-01-01 00:00:00
abstract::Proper levels of gene expression are important for normal mammalian development. Typically, altered gene dosage caused by karyotypic abnormalities results in embryonic lethality or birth defects. Segmental aneuploidy can be compatible with life but often results in contiguous gene syndromes. The ability to manipulate ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2002-02-01 00:00:00
abstract::The impact of among-environment heteroscedasticity and genetic autocorrelation on the analysis of phenotypic plasticity is examined. Among-environment heteroscedasticity occurs when genotypic variances differ among environments. Genetic autocorrelation arises whenever the responses of a genotype to different environme...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract::Segregation data were obtained for 1260 potato linkage group I-specific AFLP loci from a heterozygous diploid potato population. Analytical tools that identified potential typing errors and/or inconsistencies in the data and that assembled cosegregating markers into bins were applied. Bins contain multiple-marker data...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2003-12-01 00:00:00
abstract::The formation of dense core granules (DCGs) requires both the sorting of granule contents from other secretory proteins and a postsorting maturation process. The Tetrahymena thermophila strain SB281 fails to synthesize DCGs, and previous analysis suggested that the defect lay at or near the sorting step. Because this ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2001-12-01 00:00:00
abstract::In this article we investigate multiplicative effects between genes in relation to heterosis. The extensive literature on heterosis due to multiplicative effects between characters is reviewed, as is earlier work on the genetic description of heterosis. A two-locus diallelic model of arbitrary gene action is used to d...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1992-06-01 00:00:00
abstract::Meiosis and spore formation in the yeast Saccharomyces cerevisiae are associated with increased expression of sporulation-specific genes. One of these genes, IME2, encodes a putative protein kinase that is a positive regulator of other sporulation-specific genes. We have isolated mutations that cause reduced expressio...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1993-01-01 00:00:00
abstract::The Saccharomyces cerevisiae nuclear gene RPM2 encodes a component of the mitochondrial tRNA-processing enzyme RNase P. Cells grown on fermentable carbon sources do not require mitochondrial tRNA processing activity, but still require RPM2, indicating an additional function for the Rpm2 protein. RPM2-null cells arrest...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2000-03-01 00:00:00
abstract::Analysis of raw pooled data from distinct studies of a single question generates a single statistical conclusion with greater power and precision than conventional metaanalysis based on within-study estimates. However, conducting analyses with pooled genetic data, in particular, is a daunting task that raises importan...
journal_title:Genetics
pub_type: 杂志文章,meta分析
doi:
更新日期:2001-11-01 00:00:00
abstract::Parentage analysis is an important method that is used widely in zoological and ecological studies. Current mathematical models of parentage analyses usually assume that a population has a uniform genetic structure and that mating is panmictic. In a natural population, the geographic or social structure of a populatio...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.118.301592
更新日期:2018-12-01 00:00:00
abstract::The Genetics Society of America (GSA) Medal recognizes researchers who have made outstanding contributions to the field of genetics in the past 15 years. The 2019 GSA Medal is awarded to Bonnie L. Bassler of Princeton University and the Howard Hughes Medical Institute in recognition of her groundbreaking studies of ba...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.120.303285
更新日期:2020-06-01 00:00:00
abstract::We consider resequencing studies of associated loci and the problem of prioritizing sequence variants for functional follow-up. Working within the multivariate linear regression framework helps us to account for the joint effects of multiple genes; and adopting a Bayesian approach leads to posterior probabilities that...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.115.184572
更新日期:2016-02-01 00:00:00
abstract::Previous mathematical analyses of mutation-selection balance for metric traits assume that selection acts on the relevant loci only through the character(s) under study. Thus, they implicitly assume that all of the relevant mutation and selection parameters are estimable. A more realistic analysis must recognize that ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1985-09-01 00:00:00
abstract::A key quantity in the analysis of structured populations is the parameter K, which describes the number of subpopulations that make up the total population. Inference of K ideally proceeds via the model evidence, which is equivalent to the likelihood of the model. However, the evidence in favor of a particular value o...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.115.180992
更新日期:2016-08-01 00:00:00
abstract::The B-Peru allele of the maize b regulatory gene is unusual relative to most b alleles in that it is expressed in the aleurone layer of the seed. It is also expressed in a subset of plant vegetative tissues. Transgenic maize plants containing the B-Peru gene with the first 710 bases of upstream sequence conferred the ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1998-06-01 00:00:00
abstract::Transcription is repressed in regions of the fission yeast genome close to centromeres, telomeres, or the silent mating-type cassettes mat2-P and mat3-M. The repression involves the chromo-domain proteins Swi6 and Clr4. We report that two other chromo-domain proteins, Chp1 and Chp2, are also important for these positi...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2000-06-01 00:00:00
abstract::In somatic cells of Drosophila, the ratio of X chromosomes to autosomes (X:A ratio) determines sex and dosage compensation. The present paper addresses the question of whether germ cells also use the X:A ratio for sex determination and dosage compensation. Triploid female embryos were generated which, through the loss...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1985-03-01 00:00:00
abstract::A long-standing prediction in evolutionary biology is that organisms experience a so-called "cost of complexity" manifested as a decreasing rate of adaptation in populations as organisms or selective environments become increasingly complex. This theory assumes the ubiquity of antagonistic pleiotropy, or trade-offs in...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.119.302029
更新日期:2019-05-01 00:00:00
abstract::Genetic information can be altered by base substitutions, frameshift mutations, and addition or deletion of nucleotides. Deletions represent an important class of genetic aberration occurring at DNA sequences where it is often possible to predict the existence of intermediates of mutation. Instability within tracts of...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1995-07-01 00:00:00
abstract::Movement of transposons causes insertions, deletions, and chromosomal rearrangements potentially leading to premature lethality in Drosophila melanogaster. To repress these elements and combat genomic instability, eukaryotes have evolved several small RNA-mediated defense mechanisms. Specifically, in Drosophila somati...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.115.177196
更新日期:2016-01-01 00:00:00
abstract::Population structure parameters commonly used for diploid species are reexamined for the particular case of tetrasomic inheritance (autotetraploid species). Recurrence equations that describe the evolution of identity probabilities for neutral genes in an "island model" of population structure are derived assuming tet...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1998-10-01 00:00:00
abstract::We reported previously that the product of the DNA damage-inducible gene of Saccharomyces cerevisiae, DIN7, belongs to a family of proteins that are involved in DNA repair and replication. The family includes S. cerevisiae proteins Rad2p and its human homolog XPGC, Rad27p and its mammalian homolog FEN-1, and Exonuclea...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2000-01-01 00:00:00
abstract::The integrin family of cell surface receptors mediates cell-substrate and cell-to-cell adhesion and transmits intracellular signals. In Drosophila there is good evidence for an adhesive role of integrins, but evidence for integrin signalling has remained elusive. Each integrin is an alphabeta heterodimer, and the Dros...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1998-03-01 00:00:00
abstract::Genes in nematode and ascidian genomes frequently occur in operons--multiple genes sharing a common promoter to generate a polycistronic primary transcript--and such genes comprise 15-20% of the coding genome for Caenorhabditis elegans and Ciona intestinalis. Recent work in nematodes has demonstrated that the identity...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.110.115766
更新日期:2010-06-01 00:00:00
abstract::Thirty-five nucleotide polymorphisms were found in a 21.5-kbp region including the Est6 locus among 42 isoallelic lines extracted from a single natural population of Drosophila melanogaster. The heterozygosity per nucleotide pair was estimated to be 0.010 overall, but was lower in sequences hybridizing to transcripts ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1990-12-01 00:00:00
abstract::Mobile P elements in Drosophila melanogaster cause hybrid dysgenesis if their mobility is not repressed. One type of repression, termed P cytotype, is a complex interaction between chromosomes carrying P elements and cytoplasm and is transmitted through the cytoplasm only of females. Another type of repression is foun...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract::The breeding systems of many organisms are cryptic and difficult to investigate with observational data, yet they have profound effects on a species' ecology, evolution, and genome organization. Genomic approaches offer a novel, indirect way to investigate breeding systems, specifically by studying the transmission of...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.115.179879
更新日期:2015-11-01 00:00:00