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Chromosome instability (CIN), or continual changes in chromosome complements, is an enabling feature of cancer; however, the molecular determinants of CIN remain largely unknown. Emerging data now suggest that aberrant sister chromatid cohesion may induce CIN and contribute to cancer. To explore this possibility, we employed clinical and fundamental approaches to systematically assess the impact reduced cohesion gene expression has on CIN and cancer. Ten genes encoding critical functions in cohesion were evaluated and remarkably, each exhibits copy number losses in 12 common cancer types, and reduced expression is associated with worse patient survival. To gain mechanistic insight, we combined siRNA-based silencing with single cell quantitative imaging microscopy to comprehensively assess the impact reduced expression has on CIN in two karyotypically stable cell lines. We show that reduced expression induces CIN phenotypes, namely increases in micronucleus formation and nuclear areas. Subsequent direct tests involving a subset of prioritized genes also revealed significant changes in chromosome numbers with corresponding increases in moderate and severe cohesion defects within mitotic chromosome spreads. Collectively, our clinical and fundamental findings implicate reduced sister chromatid cohesion, resulting from gene copy number losses, as a key pathogenic event in the development and progression of many cancer types.
This article was published in the following journal.
Name: Scientific reports
ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects ...
Chromosomal instability (CIN) is one of the characteristics of cancer inherent for tumor initiation and progression, which is defined as a persistent, high rate of gain/loss of whole chromosomes. In t...
In species with genetic sex determination, dosage compensation can evolve to equal expression levels of sex-linked and autosomal genes. Current knowledge about dosage compensation has mainly been deri...
In most mammals, the male to female sex ratio of offspring is about 50% because half of the sperm contain either the Y chromosome or X chromosome. In mice, the Y chromosome encodes fewer than 700 gene...
We previously demonstrated that genome reorganization, through chromosome territory repositioning, occurred concurrently with significant changes in gene expression in normal primary human fibroblasts...
LBH589 is an oral drug that targets the myelofibrosis cells in the bone marrow and induces cell death by allowing for the expression of certain suppressed genes that are important in regul...
Cirrhosis is characterized by loss of muscle as well as fat mass, which increases morbidity and mortality before, during, and after liver transplantation. A common mechanism for the reduce...
The proposed research intends to construct a set of tissue microarrays containing different types of normal and lung cancer tissues for the study of genes associated with lung cancer. Thus...
The studied materials contains surgically specimens of two groups of patiens with non-small cell lung cancer who have received two regimens of induction (neoadjuvant) chemotherapy before t...
Two major genetic pathways leading to colorectal carcinoma can well be distinguished; the 'suppressor pathway', which is characterized by inactivation of tumor-suppressor genes and the 'mu...
A form of gene interaction whereby the expression of one gene interferes with or masks the expression of a different gene or genes. Genes whose expression interferes with or masks the effects of other genes are said to be epistatic to the effected genes. Genes whose expression is affected (blocked or masked) are hypostatic to the interfering genes.
An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.
Genetic mechanisms that allow GENES to be expressed at a similar level irrespective of their GENE DOSAGE. This term is usually used in discussing genes that lie on the SEX CHROMOSOMES. Because the sex chromosomes are only partially homologous, there is a different copy number, i.e., dosage, of these genes in males vs. females. In DROSOPHILA, dosage compensation is accomplished by hypertranscription of genes located on the X CHROMOSOME. In mammals, dosage compensation of X chromosome genes is accomplished by random X CHROMOSOME INACTIVATION of one of the two X chromosomes in the female.
Genes involved in activating the enzyme VDJ recombinase. RAG-1 is located on chromosome 11 in humans (chromosome 2 in mice) and is expressed exclusively in maturing lymphocytes.
An RNA recognition motif protein that is essential for SPERMATOGENESIS. It promotes entry of male GERM CELLS to MEIOSIS, possibly by regulating the translation of mRNAs. DAZ1 occurs within a cluster of similar genes on the Y CHROMOSOME that is prone to genetic deletions and duplications. Deletions in these genes, including DAZ1, are associated with AZOOSPERMIA and OLIGOSPERMIA.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...
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