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Epigenetics: Could cancer sometimes be an outcome of failure?

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According to new research, epigenetic regulation is required to ensure correct number of chromosomes in the daughter cells after division.

From ScienceDaily:

Normally when a cell divides, the chromosomes are segregated equally to two daughter cells. However, tumor cells frequently have either too few or too many chromosomes, leading to the incorrect expression of a number of genes. When a cell is about to divide, the cell division machinery takes hold of chromosomes by the centromere so that they may be pulled apart and one copy of each given to the daughter cells.

In the current study, researchers have shown that an epigenetic process, involving the attachment of a small protein to the histone H2B (called H2Bub1), facilitates an important structural change of the centromere immediately prior to cell division. It was previously shown that enzymes that modify histone H2B in this way also play a role in protecting against cancer. This was previously linked to defects in chromosomal repair.

Abstract Functional centromeres are essential for proper cell division. Centromeres are established largely by epigenetic processes resulting in incorporation of the histone H3 variant CENP-A. Here, we demonstrate the direct involvement of H2B monoubiquitination, mediated by RNF20 in humans or Brl1 in Schizosaccharomyces pombe, in centromeric chromatin maintenance. Monoubiquinated H2B (H2Bub1) is needed for this maintenance, promoting noncoding transcription, centromere integrity and accurate chromosomal segregation. A transient pulse of centromeric H2Bub1 leads to RNA polymerase II–mediated transcription of the centromere’s central domain, coupled to decreased H3 stability. H2Bub1-deficient cells have centromere cores that, despite their intact centromeric heterochromatin barriers, exhibit characteristics of heterochromatin, such as silencing histone modifications, reduced nucleosome turnover and reduced levels of transcription. In the H2Bub1-deficient cells, centromere functionality is hampered, thus resulting in unequal chromosome segregation. Therefore, centromeric H2Bub1 is essential for maintaining active centromeric chromatin. – Laia Sadeghi, Lee Siggens, J Peter Svensson, Karl Ekwall. Centromeric histone H2B monoubiquitination promotes noncoding transcription and chromatin integrity. Nature Structural & Molecular Biology, 2014; DOI: 10.1038/nsmb.2776

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2 Replies to “Epigenetics: Could cancer sometimes be an outcome of failure?

  1. 1

    “Could cancer sometimes be an outcome of failure?”

    Of course. The whole organism is a multitude of carefully-controlled regulations. Indeed, it is probably very often the case, if not always, that diseases, including cancer, result from a breakdown in one of the regulations.

    The reminds me of something I was thinking about just this morning — how people often talk about scientists discovering a “gene” for this or that disease. No, folks, there isn’t a “gene” for, say, heart disease. Yes, there are probably lots of genes that deal with heart function and are essential to it, but that means they are genes for heart function, not heart disease.

    It would be like me saying I’ve discovered the part for my flat tire, and that the part is a tear in the tire wall. No, there isn’t a part for a flat tire; it is a failure of a part that results in a flat tire.

    This should be clear to anyone who thinks about it long enough. Unfortunately, the lax wording and the fuzzy analysis that often accompanies evolutionary thinking can lead people to mistakenly think that a breakdown of a functional part is all just part of the evolutionary process, just as relevant as the construction of a wonderfully-functional new part. It is all just part of the same continuum of “change over time”, the thinking goes. It’s all just one big process of evolution.

    This kind of muddled thinking is what leads to comments like wd400’s on the other thread, who referred to cancer as a form of evolution. OK, sure. If by “evolution” we mean a breakdown of normally functional systems, followed by disease and death.

    But to the indoctrinated it is all just another example of “evolution” in action.

  2. 2
    jstanley01 says:

    Peter Duesberg on “Aneuploidy and Cancer“:

    The complex phenotypes of cancer, such as anaplasia, autonomous growth, metastasis, abnormal cell morphology, DNA indices ranging from 0,5 to over 2, unstable and non-clonal karyotypes and phenotypes despite its clonal origin, abnormal centrosome numbers, as well as the exceedingly slow kinetics from carcinogen to carcinogenesis of many months to decades have all been attributed to “somatic mutation”. However, it has yet to be determined whether this mutation is aneuploidy, an abnormal number of chromosomes, or gene mutation.

    A century ago Boveri proposed cancer is caused by aneuploidy, because aneuploidy correlates with cancer and because it generates “pathological” phenotypes in sea urchins. But half a century later, when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer although, (i) many carcinogens are not genotoxic, (ii) there is no functional proof that mutant genes cause cancer, and (iii) mutation is fast but carcinogenesis is exceedingly slow .

    Intrigued by the enormous mutagenic potential of aneuploidy, we undertook biochemical and biological analyses of aneuploidy and gene mutation which show that aneuploidy is probably the only mutation that can explain all aspects of carcinogenesis . On this basis we can now offer a coherent two-stage mechanism of carcinogenesis. In stage one, carcinogens cause aneuploidy which destabilizes the karyotype, and in stage two, aneuploidy evolves autocatalytically generating ever new and eventually tumorigenic karyotypes, ie. “genetic instability” . Thus cancer cells derive their unique and complex phenotypes from random chromosome number mutation, a process that is similar to regrouping assembly lines of a car factory and also to speciation. The slow kinetics of carcinogenesis reflect the low probability of generating by random chromosome reassortments a karyotype that surpasses the viability of a normal cell, similar again to natural speciation.

    The hypothesis makes several, testable predictions:

    (i) Carcinogens function as aneuploidogens. This could be tested by measuring the effect of carcinogens, such as polycyclic aromatic hydrocarbons, X-rays, and alkylating agents on the spindle apparatus, and on the karyotype of treated animal or human cells.

    (ii) Aneuploidy by unbalancing the doses of normal spindle proteins. This could be tested by transfecting diploid cells with spindle genes such as tubulin.

    (iii) Genetic instability of cancer cells. The aneuploidy hypothesis suggests that drug-resistance, the notorious obstacle of cancer chemotherapy, may be due to chromosome number mutation, rather than to conventional gene mutation . This could be tested by comparing the rates of drug-resistant variants among aneuploid cancer cells to those of their diploid normal counterparts.

    (iv) Long latent period from carcinogen to cancer. This could be studied by determining the kinetics from the introduction of aneuploidy by carcinogens until morphological transformation in vitro or tumorigenicity in animals. According to this hypothesis tumor promoters, defined as non-genotoxic substances that accelerate tumorigenesis , would enhance aneuploidization and thus shorten the latent period.

    The aneuploidy hypothesis offers new prospects of cancer prevention based on detecting aneuploidogenic substances and aneuploid preneoplastic lesions.

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