Search results for "Stability"
showing 10 items of 3085 documents
Molecular and Cellular Insights into the Development of Uterine Fibroids
2021
Uterine leiomyomas represent the most common benign gynecologic tumor. These hormone-dependent smooth-muscle formations occur with an estimated prevalence of ~70% among women of reproductive age and cause symptoms including pain, abnormal uterine bleeding, infertility, and recurrent abortion. Despite the prevalence and public health impact of uterine leiomyomas, available treatments remain limited. Among the potential causes of leiomyomas, early hormonal exposure during periods of development may result in developmental reprogramming via epigenetic changes that persist in adulthood, leading to disease onset or progression. Recent developments in unbiased high-throughput sequencing technolog…
Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice.
2007
The Cockayne syndrome B protein (CSB) has long been known to be involved in the repair of DNA modifications that block the RNA polymerase in transcribed DNA sequences (transcription-coupled repair). Recent evidence suggests that it also has a more general role in the repair of oxidative DNA base modifications such as 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG). In mammalian cells, 8-oxoG is a substrate of the repair glycosylase OGG1. Mice without this enzyme accumulate 8-oxoG in the genome and have elevated spontaneous mutation rates. To elucidate the role of CSB in the prevention of mutations by oxidative DNA base damage, we have generated mice that are deficient in Csb or Ogg1 or both ge…
Genomic instability in an interspecific hybrid of the genus Saccharomyces: a matter of adaptability
2020
Ancient events of polyploidy have been linked to huge evolutionary leaps in the tree of life, while increasing evidence shows that newly established polyploids have adaptive advantages in certain stress conditions compared to their relatives with a lower ploidy. The genus Saccharomyces is a good model for studying such events, as it contains an ancient whole-genome duplication event and many sequenced Saccharomyces cerevisiae are, evolutionary speaking, newly formed polyploids. Many polyploids have unstable genomes and go through large genome erosions; however, it is still unknown what mechanisms govern this reduction. Here, we sequenced and studied the natural S. cerevisiae × Saccharomyces…
Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair
2015
Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. In addition, classical regulation of gene expression or activity, including gene transcription to RNA followed by translation to the protein level, by transcription factors (e.g. NF-κB, HIF-1α) and mRNA binding proteins (e.g. GAPDH, HuR) is subject to redox regulation. This review will give an update of recent discoveries in this field, and specifically highlight the impact of reactive oxygen and nitrogen species on DNA repair systems that contribute to genomic stability. Emphasis will be placed …
Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair
2019
Abstract The duplication of the eukaryotic genome is an intricate process that has to be tightly safe‐guarded. One of the most frequently occurring errors during DNA synthesis is the mis‐insertion of a ribonucleotide instead of a deoxyribonucleotide. Ribonucleotide excision repair (RER) is initiated by RNase H2 and results in error‐free removal of such mis‐incorporated ribonucleotides. If left unrepaired, DNA‐embedded ribonucleotides result in a variety of alterations within chromosomal DNA, which ultimately lead to genome instability. Here, we review how genomic ribonucleotides lead to chromosomal aberrations and discuss how the tight regulation of RER timing may be important for preventin…
Checkpoint adaptation in recombination-deficient cells drives aneuploidy and resistance to genotoxic agents.
2020
Abstract Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ recombination-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibit…
Never cared for what they do. High structural stability of Guanine-quadruplexes in presence of strand-break damages
2021
AbstractDNA integrity is an important factor to assure genome stability and, more generally, cells and organisms’ viability. In presence of DNA damage, the normal cell cycle is perturbed while cells activate their repair processes. Although efficient, the repair system is not always able to ensure the complete restoration of gene integrity. In these cases, not only mutations may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold which induces apoptosis and the programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiations are the most toxic, due to their inherently difficult repair, which may lead to …
Long-Lasting Genomic Instability Following Arsenite Exposure inMammalian Cells: The Role of Reactive Oxygen Species
2011
Previously, we reported that the progeny of mammalian cells, which has been exposed to sodium arsenite for two cell cycles, exhibited chromosomal instability and concurrent DNA hypomethylation, when they were subsequently investigated after two months of subculturing (about 120 cell generations) in arsenite-free medium. In this work, we continued our investigations of the long-lasting arsenite-induced genomic instability by analyzing additional endpoints at several time points during the cell expanded growth. In addition to the progressive increase of aneuploid cells, we also noted micronucleated and multinucleated cells that continued to accumulate up to the 50th cell generation, as well a…
Tumor Hypoxia and Malignant Progression
2004
Publisher Summary This chapter discusses tumor hypoxia and malignant progression. Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen. Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels. Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors are (a) severe structural and functional abnormalities of the tumor microvessels (b) a deterioration of the diffusion geometry, …
Biological consequences of tumor hypoxia
2001
Growing evidence from experimental and clinical studies points to the fundamental, pathophysiologic role of hypoxia in solid tumors. Intratumoral hypoxia is a consequence of a structurally and functionally disturbed microcirculation, with deterioration of the diffusion geometry and of tumor-associated anemia. Hypoxia-induced changes of the proteome in the neoplastic and stroma cells may lead to neoplastic growth impairment through molecular mechanisms, resulting in cellular quiescence, differentiation, and apoptosis. Alternatively, hypoxia-induced proteome changes activating nonspecific stress response, anaerobic metabolism, angiogenesis, tissue remodeling, and change of cell contacts may p…