How Cells Handle Broken Chromosomes
ScienceDaily (Feb. 12, 2009) — Scientists from the Max Planck Institute of Biochemistry discovered a novel cellular response towards persistent DNA damage: After being recognized and initially processed by the cellular machinery, the broken chromosome is extensively scanned for homology and the break itself is later tethered to the nuclear envelope.
Thus the researchers uncovered a surprising feature of how DNA strand breaks can be handled. Their unexpected findings have important implications for the understanding of DNA repair mechanisms.
The central molecule for life is DNA, which constitutes the genetic blueprint of our organism. However, this precious molecule is constantly threatened by miscellaneous damage sources. DNA damage is a cause of cancer development, degenerative diseases and aging. The most dangerous and lethal type of DNA-damage is the DNA double strand break (DSB). A single DSB is enough to kill a cell or cause chromosomal aberrations leading to cancer. Therefore, cells have evolved elaborate DNA repair systems that are fundamental for human health.
Words like "evolve... ...for" betrays the author's stealth teleology. Materialists should handcuff this "non-scientist" for smuggling in teleological features into evolutionary thought
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DSBs can be repaired by error-prone non-homologous end joining, a pathway in which the DSB ends are simply fused together again. The alternative repair pathway, called homologous recombination, is mostly error-free and needs homologous DNA sequences to guide repair. A vast amount of research, by many scientists around the world, has provided us with a detailed picture of how the DNA damage is recognized and finally repaired. However, so far little was known, how homologous sequences are found and how cells react when DNA breaks persist.
Now, scientists around Stefan Jentsch, head of the Department of Molecular Cell Biology, were able to shed light on these questions, as they report in the upcoming issue of Molecular Cell.
The scientists modified a yeast strain in which a DSB can be induced and followed over time. Moreover, they managed to label the DNA-break for microscopic studies. Using high-resolution digital imaging, they observed after a few hours a directed movement of the break to the nuclear envelope. Jentsch and colleagues speculate that this tethering to the nuclear envelope could be a safety measure of cells to prevent erroneous and unwanted recombination events, which can have catastrophic consequences like cancer development or cell death.
Marian Kalocsay and Natalie Hiller, who conducted the study as part of their PhD-thesis research, then set out to unravel the molecular details of how a persistent DSB is recognized, processed and – at last - relocated to the nuclear envelope.
Using a high resolution method – the so called chip-on-chip technique - which allowed to investigate repair factor recruitment to DNA in unprecedented details, the researchers made a surprising observation: In an apparent attempt to find homology and repair the DSB, a protein called Rad51 (or “recombinase”) begins within one hour to accumulate and to spread bi-directionally from the break, covering after a short time the entire chromosome – a much larger area than supposed before. “Intriguingly, Rad51 spreading only occurs on the chromosome where the break resides and does not “jump” to other chromosomes”, says Kalocsay. As to the researchers knowledge, this is the first in vivo description of ongoing chromosome-wide homology search, which is the most mysterious event in DSB repair. Therefore, this finding has important implications for the understanding of DNA repair by homologous recombination.
Furthermore, Kalocsay and Hiller identified a novel important player in the DNA-damage response that is essential for Rad51 activation as well as for the relocation of DSBs to the nuclear envelope: the histone variant H2A.Z. In early stages of DNA repair it is incorporated into DNA near the DSBs and is essential there for the initiation of the following repair mechanisms. Later on, the attachment of the small modifying protein SUMO to H2A.Z plays an important role in the tethering of the break to the nuclear envelope. “Moreover, cells lacking H2A.Z are severely sensitive to DSBs, thus revealing H2A.Z as an important and novel factor in DSB-repair”, explains Hiller.
Can't wait for the molecular simulation for this mechanism.
Viruses often get a bad wrap. No one knows the origins of viruses though.
Exogenous accidents or endogenous retroviruses gone wild. The second one sounds more plausible.
Research On Viral Origins Suggests New Definition Of Virus May Be Needed
ScienceDaily (Feb. 16, 2009) — The strange interaction of a parasitic wasp, the caterpillar in which it lays its eggs and a virus that helps it overcome the caterpillar’s immune defenses has some scientists rethinking the definition of a virus.
In an essay in the journal Science, Donald Stoltz, a professor of microbiology and immunology at Dalhousie University, in Halifax, Nova Scotia, and James Whitfield, a professor of entomology at the University of Illinois, report that a new study also appearing in Science shows how the diverse ways in which viruses operate within and among the organisms they encounter may not be fully appreciated.
Indeed. Consider the following functions of endogenous retroviruses and related elements.
1) Independent envelope genes from unrelated ERV families regulate trophoblast differentiation and syncytia formation during synepitheliochorial placentation. Are there examples of Eutheria that are capable of reproduction without ERVs?
Humans (primates): HERV-W and HERV-FRD
Mice (Rodentia): Syncytin-A and -B
Sheep (Artiodactyla): enJSRV
2) Retroelement formatting of the genome [1].
System architectures formatting by retroelements and other repeat elements possibly have an effect on morphological, physiological and reproductive function.
3) LTRs play a fundamental role in gene expression
Independently acquired LTRs have assumed regulatory roles for orthologous genes [2].
An LTR is the dominant promoter in the colon, indicating that this ancient retroviral element has a major impact on gene expression [3].
LTR class I endogenous retrovirus (ERV) retroelements impact considerably on the transcriptional network of human tumor suppressor protein p53 (guardian of the genome) [4].
4) Role in autoimmunity [5].
Disease associations have been established, however there is as yet no proven definite causative association between HERVs and disease.
a) Human endogenous retroviruses can encode superantigenic activity
b) Transcriptional activation. HERVs may act as insertional mutagens or cis-regulatory elements causing activation, inhibition, or alternative splicing of cellular genes involved in immune function.
c) Molecular mimicry. Production of neo-antigens by modification of cellular components.
d) Epitope spreading.
e) Activation of innate immunity through pattern recognition receptors.
[1] von Sternberg R, Shapiro JA. How repeated retroelements format genome function. Cytogenet Genome Res. 2005;110(1-4):108-116.
[2] Romanish MT, Lock WM, van de Lagemaat LN, Dunn CA, et al. Repeated recruitment of LTR retrotransposons as promoters by the anti-apoptotic locus NAIP during mammalian evolution. PLoS Genet. 2007 Jan 12;3(1):e10.
[3] Dunn CA, Medstrand P, Mager DL. An endogenous retroviral long terminal repeat is the dominant promoter for human beta1,3-galactosyltransferase 5 in the colon. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12841-12846.
[4] Wang T, Zeng J, Lowe CB, Sellers RG, Salama SR, Yang M, et al. Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18613-18618.
[5] Colmegna I, Garry RF. Abstract Role of endogenous retroviruses in autoimmune diseases. Infect Dis Clin North Am. 2006 Dec;20(4):913-929.
This study just contributes to more fascinating functions of these retroviral elements.
The study, from a team of researchers led by the Université François Rabelais, in Tours, France, found that the genes that encode a virus that helps wasps successfully parasitize caterpillars are actually integrated into the wasps’ own chromosomes. These genes, which they show to be related to those from another known group of viruses, are an indivisible part of the wasp’s genetic heritage; they are passed down from one generation to another of parasitoid wasps.
“Many virology texts won’t even mention polydnaviruses,” Whitfield said. “The issue we bring up is: Do we want to call these viruses? And if not, why not? Because they certainly started out as viruses. And if so, then we have to change the definition of viruses to somehow specify what it is that a virus has to contain, and what it has to do, to be considered a virus.”
ERV research at present is rich with speculations and it is a fertile ground for new and exciting ideas regarding their importance and functionality. (previously thought to randomly integrated junk)
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