Intelligently designed apparatus for teaching mountaineers.
William Heath-Robinson
One thing you can depend on with creationism's putative designer is that there will never be a simple solution when there is a more complicated way to solve the problem it just created, and just like William Heath-Robinson, it will try to use pre-existing structures that were designed for an entirely different function, like a pile of books under the legs of a ladder to make it tall enough, and every piece of string holding things together will have knots in it.
And when we look beneath the superficial resemblance of design in, for example, a living cell, we find all manner of if-it-works-it'll-do solutions to problems, like the solution to the problem of breaking DNA that a team of scientists, led by Kaspar Burger, from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, have discovered.
The problem arises of course because the method for replicating DNA as cells divide is poorly designed and unnecessarily complicated in the first place. If the putative designer had devised a more sensible method for replicating cells in multicellular organisms than that used for replicating single cells where the whole genome needs to be replicated, many of the problems of erroneous copying wouldn't arise because only a small subset of the genome is needed for specialised cells.
What is the current thinking on how cells detect and repair broken DNA and what happens when it goes wrong? Cells have highly evolved systems to detect and repair DNA damage, especially breaks in the DNA strands, which are critical to maintain genetic integrity and prevent diseases such as cancer. Here’s a summary of the current understanding of these mechanisms:But, having stuck with an unnecessarily and error-strewn method, naturally our bungling designer set about designing another layer of complexity to mend the broken DNA. What the researchers have discovered is a mechanism that is mediated by a long length of RNA knowns as long non-coding RNA (lncRNA). lncRNA is of course coded for by lengths of DNA that are regarded as redundant because they don't code for proteins.
DNA Damage Detection and Repair Mechanisms
- Types of DNA Damage:
- Single-strand breaks (SSBs): Only one strand of the DNA double helix is broken.
- Double-strand breaks (DSBs): Both strands are broken, which is particularly dangerous as it can lead to loss of genetic information.
- Detection of DNA Damage:
Cells use specialized protein complexes to recognize DNA breaks. The process generally follows these steps:
- Sensor proteins: These proteins detect damaged DNA. For example, ATM (Ataxia Telangiectasia Mutated) is primarily responsible for detecting double-strand breaks, while ATR (ATM and Rad3-Related) is activated by single-strand breaks and stalled replication forks.
- Signal transduction: Once damage is detected, these sensors activate a cascade of signaling molecules that mobilize the repair machinery. Proteins like p53, Chk1, and Chk2 play key roles in coordinating this response by halting the cell cycle and facilitating repair.
- Repair Pathways:
Cells use different mechanisms depending on the type of break:
- For Single-Strand Breaks:
- The base excision repair (BER) pathway is the main mechanism for fixing minor damage, like oxidative damage or small chemical alterations to the DNA.
- The nucleotide excision repair (NER) pathway corrects larger, bulkier lesions such as those caused by UV radiation.
- For Double-Strand Breaks:
- Non-homologous end joining (NHEJ): This is a quick repair pathway that rejoins the broken DNA ends without needing a template. It’s error-prone because it can introduce small mutations.
- Homologous recombination (HR): This is a more accurate process that uses a sister chromatid (present after DNA replication) as a template to repair the break without loss of genetic information.
What Happens When Repair Goes Wrong?
- Mutations and Cancer:
If DNA damage is not properly repaired, it can lead to mutations—changes in the DNA sequence. These mutations can affect genes involved in cell growth and division (oncogenes or tumor suppressors), leading to uncontrolled cell proliferation and cancer. For example:
- p53 mutations are very common in cancers and occur when the cell’s ability to trigger apoptosis (cell death) after DNA damage is lost.
- BRCA1/BRCA2 mutations impair homologous recombination, leading to breast and ovarian cancers.
- Genomic Instability:
When cells can’t repair DNA damage correctly, they accumulate mutations over time. This creates genomic instability, which is a hallmark of cancer cells. Genomic instability can lead to chromosomal rearrangements, duplications, or deletions, contributing to tumor progression.- Aging and Degenerative Diseases:
Inefficient DNA repair is also linked to aging. Over time, as more DNA damage accumulates without being repaired, cells lose their ability to function properly. This can contribute to age-related diseases such as neurodegenerative disorders (e.g., Alzheimer’s, Parkinson’s).- Developmental Disorders:
Some inherited diseases result from defects in DNA repair mechanisms:
- Xeroderma Pigmentosum (XP): Individuals with XP have a defect in the nucleotide excision repair pathway, leading to extreme sensitivity to UV light and a high risk of skin cancers.
- Ataxia Telangiectasia (AT): A defect in the ATM gene affects the ability to repair double-strand breaks, leading to neurodegeneration, immune system deficiencies, and cancer.
Emerging Research:
Recent research focuses on:
- Targeting DNA repair pathways for cancer treatment: Inhibitors of repair proteins like PARP (poly ADP-ribose polymerase), which are involved in single-strand break repair, are used to treat cancers with defective homologous recombination (e.g., BRCA-mutated cancers).
- Understanding DNA damage responses in aging: This research aims to slow down age-related degeneration by enhancing DNA repair processes.
- Synthetic lethality approaches: By targeting specific weaknesses in cancer cells' repair pathways, researchers can kill cancer cells while sparing normal cells.
Overall, when DNA repair goes wrong, it can lead to various diseases, including cancer, premature aging, and developmental disorders, highlighting the critical role these processes play in cellular health.
This will thrill creationists who argue that there is no such thing as redundant, or 'junk' DNA because an intelligent designer wouldn't have created it [sic], until they realise this use of it is yet more complexity to solve a problem of poor design, and an example of exaptation of redundant structure - the mechanism that gives rise to 'irreducibly complex' structures without the need for intelligent intervention.
The team have just published their findings, open access, in the journal Genes & Development and announced it in a Julius-Maximilians-Universität Würzburg, news release:
How Cells Recognize and Repair DNA Damage
Genome instability can cause numerous diseases. Cells have effective DNA repair mechanisms at their disposal. A research team at the University of Würzburg has now gained new insights into the DNA damage response.
Whenever cells divide, there is a high risk of damage to the genetic material. After all, the cell has to duplicate its entire genetic material and copy billions of genetic letters before it divides. This repeatedly results in “reading errors” of the genome. However, other factors are also responsible for the accumulation of DNA damage in the course of a person's life: exposure to sun light, alcohol and cigarettes are just a few examples of factors that are known to damage the genetic material and thus can cause cancer, among other things.
Of course, the cell is not powerless in the face of such lesions. It has an extensive catalog of cellular mechanisms that are set in motion following DNA damage. DNA damage response, or DDR for short, is the technical term for this. Specific signaling pathways usually initiate the immediate recognition and repair of DNA damage, thus ensuring the survival of the cell.
A new look at the DNA damage response
A team of scientists from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has now taken a closer look at one of these signaling pathways. The group has identified a new mechanism of the DNA damage response that is mediated via an RNA transcript. Their results help to broaden the conceptual view on the DNA damage response and to link it more closely with RNA metabolism.
Dr. Kaspar Burger, junior research group leader at the Department of Biochemistry and Molecular Biology, was responsible for this study. The group has published the results of their investigations in the journal Genes & Development.
RNA transcripts as regulators of genome stability
In our study, we focused on so-called long non-coding RNA transcripts. Previous data suggest that some of these transcripts act as regulators of genome stability.
Our hypothesis was that RNA metabolism involves NEAT1 in the DNA damage response in order to ensure the stability of the genome.
We were able to show that DNA double-strand breaks increase both the number of NEAT1 transcripts and the amount of N6-methyladenosine marks on NEAT1.
Kaspar Burger, lead-author
Department of Biochemistry and Molecular Biology
Biocenter of the University of Würzburg
Würzburg, Germany.
The study focused on the nuclear enriched abundant transcript 1 - also known as NEAT1 - which is found in high concentrations in many tumor cells. NEAT1 is also known to react to DNA damage and to cellular stress. However, its exact role in the DNA damage response was previously unclear.
To test this hypothesis, the research group experimentally investigated how NEAT1 reacts to serious damage to the genome - so-called DNA double-strand breaks - in human bone cancer cells.
RNA modification marks are often deregulated in cancer cells
Methyladenosine marks on RNA transcripts are a topic that scientists have not been dealing with for very long. They fall into the area of epitranscriptomics - the field of biology that deals with the question of how RNA modifications are involved in the regulation of gene expression. Methyl groups play a key role in this. It is known, for example, that RNA modifications are often misplaced in cancer cells.
NEAT1 releases an DNA repair factor
The experiments conducted by Kaspar Burger and his team show that the frequent occurrence of DNA double-strand breaks causes excessive methylation of NEAT1, which leads to changes in the NEAT1 secondary structure. As a result, highly methylated NEAT1 accumulates at some of these lesions to drive the recognition of broken DNA. In turn, experimentally induced suppression of NEAT1 levels delayed the DNA damage response, resulting in increased amounts of DNA damage.
NEAT1 itself does not repair DNA damage. However, as the Würzburg team discovered, it enables the controlled release and activation of an RNA-binding DNA repair factor. In this way, the cell can recognize and repair DNA damage highly efficiently.
According to the scientists, knowledge about the role of NEAT1 methylation in the recognition and repair of DNA damage could open up new therapeutic options for tumors with high NEAT1 expression. However, it must first be clarified whether these results, which were obtained in simple cell systems, can also be transferred to complex tumor models.
Kaspar Burger's research was supported by the German Cancer Aid and the Mildred Scheel Early Career Center for Cancer Research (MSNZ) in Würzburg.
Original publicationVictoria Mamontova, Barbara Trifault, Anne-Sophie Gribling-Burrer, Patrick Bohn, Lea Boten, Pit Preckwinkel, Peter Gallant, Daniel Solvie, Carsten P. Ade, Dimitrios Papadopoulos, Martin Eilers, Tony Gutschner, Redmond P. Smyth, Kaspar Burger.
NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4.
Genes & Development
AbstractSo, when we look beneath the appearance of design, we find a ramshackle, error-strewn layer of complexity, utilising otherwise redundant RNA, just to repair the mistakes of a ramshackle, error-strewn mechanism for replicating cells. And when that doesn't work, we get cancer, premature aging and other developmental disorders.
Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone acetylation at DSBs. Our data suggest a direct role for NEAT1 in DDR.
Victoria Mamontova, Barbara Trifault, Anne-Sophie Gribling-Burrer, Patrick Bohn, Lea Boten, Pit Preckwinkel, Peter Gallant, Daniel Solvie, Carsten P. Ade, Dimitrios Papadopoulos, Martin Eilers, Tony Gutschner, Redmond P. Smyth, Kaspar Burger.
NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4.
Genes & Development October 3, 2024, doi:10.1101/gad.351913.124
Copyright: © 2024 The authors.
Published by Cold Spring Harbor Laboratory Press. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
Or was that the plan all along?
To creationists, this looks like the work of a brilliant, omniscient, omnipotent, all-loving master-designer - which probably tells us more about creationists than they would like us to know.
The take-away lesson is to never allow a creationist anywhere near a drawing board, especially where critical designs are involved.
The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
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