Article

Diverse system stresses: common mechanisms of chromosome fragmentation. Cell Death Dis 2:e178-e186

The Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Cell Death & Disease (Impact Factor: 5.01). 06/2011; 2(6):e178. DOI: 10.1038/cddis.2011.60
Source: PubMed

ABSTRACT

Chromosome fragmentation (C-Frag) is a newly identified MCD (mitotic cell death), distinct from apoptosis and MC (mitotic catastrophe). As different molecular mechanisms can induce C-Frag, we hypothesize that the general mechanism of its induction is a system response to cellular stress. A clear link between C-Frag and diverse system stresses generated from an array of molecular mechanisms is shown. Centrosome amplification, which is also linked to diverse mechanisms of stress, is shown to occur in association with C-Frag. This led to a new model showing that diverse stresses induce common, MCD. Specifically, different cellular stresses target the integral chromosomal machinery, leading to system instability and triggering of MCD by C-Frag. This model of stress-induced cell death is also applicable to other types of cell death. The current study solves the previously confusing relationship between the diverse molecular mechanisms of chromosome pulverization, suggesting that incomplete C-Frag could serve as the initial event responsible for forms of genome chaos including chromothripsis. In addition, multiple cell death types are shown to coexist with C-Frag and it is more dominant than apoptosis at lower drug concentrations. Together, this study suggests that cell death is a diverse group of highly heterogeneous events that are linked to stress-induced system instability and evolutionary potential.

Download full-text

Full-text

Available from: Henry Heng
  • Source
    • "As MN may merge back with the main nucleus, this will result in the rearranged chromosomes becoming a part of the genome as described by Janssen et al. [2011]. cell death called chromosome fragmentation [Stevens et al. 2011; Stevens et al. 2007]. Notably, unbalanced partial chromosomal losses and gains have also been observed in fragmented aneuploid embryos and not euploid embryos, to suggest a relationship between sub-chromosomal instability and aneuploidy in the human embryo [Chavez et al. 2012; Vanneste et al. 2009]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pre-implantation embryo development in mammals begins at fertilization with the migration and fusion of the maternal and paternal pro-nuclei, followed by the degradation of inherited factors involved in germ cell specification and the activation of embryonic genes required for subsequent cell divisions, compaction, and blastulation. The majority of studies on early embryogenesis have been conducted in the mouse or non-mammalian species, often requiring extrapolation of the findings to human development. Given both conserved similarities and species-specific differences, however, even comparison between closely related mammalian species may be challenging as certain aspects, including susceptibility to chromosomal aberrations, varies considerably across mammals. Moreover, most human embryo studies are limited to patient samples obtained from in vitro fertilization (IVF) clinics and donated for research, which are generally of poorer quality and produced with germ cells that may be sub-optimal. Recent technical advances in genetic, epigenetic, chromosomal, and time-lapse imaging analyses of high quality whole human embryos have greatly improved our understanding of early human embryogenesis, particularly at the single embryo and cell level. This review summarizes the major characteristics of mammalian pre-implantation development from a chromosomal perspective, in addition to discussing the technological achievements that have recently been developed to obtain this data. We also discuss potential translation to clinical applications in reproductive medicine and conclude by examining the broader implications of these findings for the evolution of mammalian species and cancer pathology in somatic cells.
    Full-text · Article · Sep 2015 · Systems biology in reproductive medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: While our understanding of gene-based biology has greatly improved, it is clear that the function of the genome and most diseases cannot be fully explained by genes and other regulatory elements. Genes and the genome represent distinct levels of genetic organization with their own coding systems; Genes code parts like protein and RNA, but the genome codes the structure of genetic networks, which are defined by the whole set of genes, chromosomes and their topological interactions within a cell. Accordingly, the genetic code of DNA offers limited understanding of genome functions. In this perspective, we introduce the genome theory which calls for the departure of gene-centric genomic research. To make this transition for the next phase of genomic research, it is essential to acknowledge the importance of new genome-based biological concepts and to establish new technology platforms to decode the genome beyond sequencing.
    Full-text · Article · May 2011 · Genomics
  • [Show abstract] [Hide abstract]
    ABSTRACT: The recently introduced genome theory of cancer evolution provides a new framework for evolutionary studies on cancer. In particular, the established relationship between the large number of individual molecular mechanisms and the general evolutionary mechanism of cancer calls upon a change in our strategies that have been based on the characterization of common cancer gene mutations and their defined pathways. To further explain the significance of the genome theory of cancer evolution, a brief review will be presented describing the various attempts to illustrate the evolutionary mechanism of cancer, followed by further analysis of some key components of somatic cell evolution, including the diversity of biological systems, the multiple levels of information systems and control systems, the two phases (the punctuated or discontinuous phase and gradual Darwinian stepwise phase) and dynamic patterns of somatic cell evolution where genome replacement is the driving force. By linking various individual molecular mechanisms to the level of genome population diversity and tumorigenicity, the general mechanism of cancer has been identified as the evolutionary mechanism of cancer, which can be summarized by the following three steps including stress-induced genome instability, population diversity or heterogeneity, and genome-mediated macroevolution. Interestingly, the evolutionary mechanism is equal to the collective aggregate of all individual molecular mechanisms. This relationship explains why most of the known molecular mechanisms can contribute to cancer yet there is no single dominant mechanism for the majority of clinical cases. Despite the fact that each molecular mechanism can serve as a system stress and initiate the evolutionary process, to achieve cancer, multiple cycles of genome-mediated macroevolution are required and are a stochastically determined event. Finally, the potential clinical implications of the evolutionary mechanism of cancer are briefly reviewed.
    No preview · Article · Dec 2011 · Advances in Cancer Research
Show more