tag:theconversation.com,2011:/ca/topics/dna-replication-8157/articlesDNA replication – The Conversation2019-12-05T01:45:05Ztag:theconversation.com,2011:article/1277282019-12-05T01:45:05Z2019-12-05T01:45:05ZTick, tock… how stress speeds up your chromosomes’ ageing clock<figure><img src="https://images.theconversation.com/files/305098/original/file-20191204-70126-7cple3.jpg?ixlib=rb-1.1.0&rect=0%2C216%2C4380%2C3244&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">At a molecular level, stresses and strains can make your body clock break into a sprint.</span> <span class="attribution"><span class="source">Lightspring/Shutterstock</span></span></figcaption></figure><p>Ageing is an inevitability for all living organisms, and although we still don’t know exactly why our bodies gradually grow ever more decrepit, we are starting to grasp how it happens.</p>
<p>Our new research, <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/ele.13426">published in Ecology Letters</a>, pinpoints factors that influence one of the most important aspects of the ageing process, at the fundamental level of our DNA. It suggests how stress can cause the biochemical body clock built into our chromosomes to tick faster.</p>
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Read more:
<a href="https://theconversation.com/the-search-to-extend-lifespan-is-gaining-ground-but-can-we-truly-reverse-the-biology-of-ageing-75127">The search to extend lifespan is gaining ground, but can we truly reverse the biology of ageing?</a>
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<p>DNA - the genetic material in our cells - does not float freely in cells’ nuclei, but is organised into clumps called chromosomes. When a cell divides and produces a replica of itself, it has to make a copy of its DNA, and because of the way this process works, a tiny portion is always lost at one end of each DNA molecule. </p>
<p>To protect vital portions of DNA from being lost in the process, the ends of chromosomes are capped with special sequences called <a href="https://www.britannica.com/science/telomere">telomeres</a>. These are gradually whittled away during successive cell divisions.</p>
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<span class="caption">Telomeres (highlighted in white) are like molecular buffers for your chromosomes.</span>
<span class="attribution"><a class="source" href="http://science.nasa.gov/media/medialibrary/2006/03/16/22mar_telomeres_resources/caps.gif">US Dept of Energy Human Genome Program</a></span>
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<p>This gradual loss of telomeres acts like a cellular clock: with each replication they get shorter, and at a certain point they become too short, forcing the cell into a programmed death process. The key question is what this process, which plays out on a cellular level, actually means for our mortality. Does the fate of individual cells really matter so much? Does the ticking telomere clock really count down the remaining time our bodies have to live?</p>
<p>Cellular ageing is just one of many components of ageing - but it’s one of the most important. Gradual deterioration of our body’s tissues, and the irreversible death of our cells, are responsible for the most conspicuous effects of ageing such as loss of physical fitness, deterioration of connective tissues leading to skin wrinkles, or neurodegenerative diseases such as Parkinson’s disease.</p>
<h2>What makes us tick?</h2>
<p>Another crucial question is: are there factors that speed up or slow down the loss of our ticking telomeres? </p>
<p>So far, our answers to this question have been incomplete. Studies have provided glimpses of possible mechanisms, suggesting that things like <a href="https://science.sciencemag.org/content/347/6220/436/tab-figures-data">infections</a> or even <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/jeb.12479">dedicating extra energy to reproduction</a> might accelerate telomere shortening and speed up cellular ageing. </p>
<p>This evidence is piecemeal, but these factors all seem to have one thing in common: they cause “physiological stress”. Broadly speaking, our cells are stressed when their biochemical processes are disrupted, either by a lack of resources or for some other reason. If cells lose too much water, for example, we might say they are in “dehydration stress”.</p>
<p>More familiar types of stress also count. Tiredness and overwork put us under chronic stress, as does feeling anxious for prolonged periods. <a href="https://www.sciencedaily.com/releases/2018/07/180712141715.htm">Lack of sleep</a> or <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763246/">emotional stress</a> can alter internal cellular pathways, including telomere functioning.</p>
<p>With this in mind, we asked ourselves one simple question. Can various types of stress experienced by an individual actually accelerate their rate of ageing?</p>
<h2>Stress and strain</h2>
<p>In our research, led by my colleague Marion Chatelain of the University of Warsaw (currently University of Innsbruck), we chose to look at this question as broadly as possible. Many studies have looked at this problem in specific species, such as mice, rats, and various fish and bird species (both wild and in the lab). We compiled the available evidence into a summary of the existing knowledge, across all vertebrate organisms studied so far.</p>
<p>The emerging picture clearly suggests that telomere loss is profoundly impacted by stress. All else being equal, stress does indeed hasten telomere loss and accelerate the internal cellular clock. </p>
<p>Importantly, the type of stress matters: by far the strongest negative impact is caused by pathogen infections, competition for resources, and intensive investment in reproduction.</p>
<p>Other stressors, such as poor diet, human disturbance or urban living, also hastened cellular ageing, although to a lesser extent.</p>
<h2>Getting radical</h2>
<p>A natural question arises: what makes stress exert such a powerful influence on cellular clocks? Is there a single mechanism, or many? Our analysis may have identified one possible candidate: “oxidative stress”. </p>
<p>When cells are stressed, this often manifests itself through an accumulation of oxidising molecules, such as <a href="https://theconversation.com/health-check-the-untrue-story-of-antioxidants-vs-free-radicals-15920">free radicals</a>. Residing at the exposed ends of our chromosomes, telomeres are perfect targets for attack by these chemically reactive molecules. </p>
<p>Our analysis suggests that, regardless of the type of stress experienced, this oxidative stress might be the actual biochemical process that links stress and telomere loss. As to whether this means that we should eat more <a href="https://www.britannica.com/science/antioxidant">antioxidants</a> to guard our telomeres, this certainly requires more research.</p>
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<a href="https://theconversation.com/health-check-the-untrue-story-of-antioxidants-vs-free-radicals-15920">Health Check: the untrue story of antioxidants vs free radicals</a>
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<p>I know what you’re wondering: does this mean we have discovered the secret of ageing? Can we use this knowledge to slow the ageing process or stop it in its tracks? The short answer is: no. </p>
<p>Ageing is too fundamental to our biology to get rid of it completely. But our study does underline an important truth: by reducing stress, we can do our bodies a big favour. </p>
<p>In the modern world, it is hard to escape stress completely, but we can make everyday decisions to reduce it. Get enough sleep, drink enough water, eat healthily and don’t push yourself too hard. It won’t buy you eternal life, but it should keep your cells ticking along nicely.</p>
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<p><em>The author thanks his colleagues <a href="https://www.uibk.ac.at/ecology/staff/persons/chatelain.html.en">Marion Chatelain</a> and <a href="https://cent.uw.edu.pl/en/person/prof-marta-szulkin/">Marta Szulkin</a> for their contributions to this article and the research on which it is based.</em></p><img src="https://counter.theconversation.com/content/127728/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Szymek Drobniak works for the University of New South Wales and the Jagiellonian University in Poland. He receives funding from the Australian Research Council. He is also a member of the Evolutionary Knowledge for Everyone association, the European Society for Evolutionary Biology and the Society for the Study of Evolution.</span></em></p>Emerging evidence suggests that prolonged stress exposure can accelerate the ticking rate of an internal cellular clock. By doing so, stress can contribute to faster ageing and body deterioration.Szymek Drobniak, DECRA Fellow, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1159562019-04-25T10:44:17Z2019-04-25T10:44:17ZDNA as you’ve never seen it before, thanks to a new nanotechnology imaging method<figure><img src="https://images.theconversation.com/files/270811/original/file-20190424-121241-96r4oz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A map of DNA with the double helix colored blue, the landmarks in green, and the start points for copying the molecule in red.</span> <span class="attribution"><span class="source">David Gilbert/Kyle Klein</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=609&fit=crop&dpr=1 600w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=609&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=609&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=766&fit=crop&dpr=1 754w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=766&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=766&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">The first revealing image of DNA taken using X-ray diffraction.</span>
<span class="attribution"><a class="source" href="http://www-project.slac.stanford.edu/wis/images/photo_51.jpg">Raymond Gosling/King's College London</a></span>
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<span class="caption">The helical DNA staircase. The building blocks of DNA, or bases, lie horizontally between the two spiraling strands.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/d/db/DNA_orbit_animated_static_thumb.png">Richard Wheeler</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>For biologists everywhere, April 25 is auspicious. It is <a href="https://www.genome.gov/dna-day">DNA Day</a> and commemorates the date in 1953 when scientists <a href="https://doi.org/10.1038/171737a0">Francis Crick</a>, <a href="https://doi.org/10.1038/171740a0">Rosalind Franklin</a>, <a href="https://doi.org/10.1038/171737a0">James Watson</a> and <a href="https://doi.org/10.1038/171738a0">Maurice Wilkins</a> published seminal scientific papers describing the helical structure of the DNA molecule. In 2003, April 25 was used to announce the completion of the <a href="https://www.genome.gov/human-genome-project">Human Genome Project</a>. Now annual festivities on this day celebrate the molecule of life with new discoveries. What better time to provide a new picture of DNA.</p>
<p>I am DNA DAVE (or at least my license plate since 1984 says so), and one of the things <a href="http://gilbertlab.bio.fsu.edu">my lab</a> likes to do is to “see” DNA. We take images of DNA so that we can directly measure things that are difficult to quantify using indirect methods that usually involve sequencing the four chemical units of DNA, called bases. </p>
<p>For example, I would like to know where on each chromosome the process of DNA replication begins. Error-free duplication of DNA is essential for producing healthy cells. When this process is incomplete or disrupted, the result can cause cancer and other diseases.</p>
<p>In our image that familiar double helix staircase is not visible because this perspective is zoomed out – like looking at the map of a country versus a city. Also each of these molecules is equivalent to 50,000 turns of the helical staircase – a substantial segment of a human chromosome. </p>
<h2>Making a map of DNA</h2>
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<span class="caption">Single strands of DNA are colored blue. Green marks the location of specific landmarks. Red highlights the locations where DNA replication is beginning.</span>
<span class="attribution"><span class="source">David Gilbert/Kyle Klein</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
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<p>This image, taken with a device called the Bionano Genomics Saphyr imager, features individual DNA molecules – colored in blue, green and red. These strands of DNA have been aligned by threading them through narrow tubes – called nanochannels – that fit only one piece of DNA. As the DNA slips into the tube, the strands straighten. </p>
<p>The whole DNA molecule is colored blue and the green tick marks are landmarks – or specific sequences of DNA that occur on average every 4,500 base pairs. The pattern of landmarks provide a unique fingerprint which tells us where we are along the length of a chromosome. The red fluorescent blips tag the locations where the DNA has begun to replicate. These sites are called “origins of replication” and are where the DNA first unwinds so that the duplication process can start. </p>
<p>Researchers at <a href="https://bionanogenomics.com/">Bionano Genomics</a> in San Diego developed this nanochannel technology to chart regions of chromosomes that were otherwise unmappable, due to tricky genetic sequences that make it difficult to determine the order of the four bases. This device solved the problem by “looking” at the arrangement of sequences on one molecule at a time and is able to read 30 billion base pairs in one hour – the equivalent of 10 human genomes. </p>
<p>My team and that of <a href="https://www.umassmed.edu/rhindlab/">Nick Rhind at the University of Massachusetts</a> recognized that this nanochannel technology would allow us to conduct an experiment never attempted before: map all the locations where DNA replication begins simultaneously on millions of single DNA fibers. </p>
<p>Before a cell can divide into two independent cells, the DNA must make a copy of itself so that each one receives a complete set of chromosomes. To understand how the genetic material is duplicated it is essential to know where along the chromosome the process begins. That has been the greatest challenge to studying how the replication of our own chromosomes takes place and consequently what is going wrong in so many diseases, like cancer, in which replication goes awry. </p>
<h2>DNA replication and cancer</h2>
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<span class="caption">Every time a cell divides the DNA double helix must duplicate itself to provide a copy of the genetic instructions to both cells.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/mechanism-dna-replication-one-molecule-produced-759392011?src=z6-3R29O9C2ja3mWxmEeiQ-1-0">Soleil Nordic/Shutterstock.com</a></span>
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<p>Origins of replication have been elusive because they occur at many sites on different molecules so we need to look at single DNA molecules to detect them. Although scientists have been able to see single DNA molecules since the early 1960s, we could not tell where in the chromosomes any molecule came from so we could not map anything. </p>
<p>Kyle Klein, <a href="http://gilbertlab.bio.fsu.edu/current.php">a Ph.D. student in my lab</a>, labeled living human stem cells with red fluorescent molecules that marked locations where DNA replication was taking place, which were mapped with the Bionano device. These images were then superimposed onto the blue and green DNA maps of the same DNA molecules. </p>
<p><a href="https://www.biorxiv.org/content/10.1101/214841v1">We expect this method to completely transform</a> our understanding of how human chromosomes replicate. Moreover, since most chemotherapy drugs for cancer treatment and most carcinogens – or cancer-causing chemicals – in our environment work by attacking DNA when it replicates, we expect this method to provide a rapid and comprehensive test for how these chemicals disrupt DNA replication. We also hope it reveals how we might alleviate these negative consequences, and how we might develop better and less toxic chemotherapy treatments.</p><img src="https://counter.theconversation.com/content/115956/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David M. Gilbert receives funding from the NIH (National Institute of General Medical Science, National Genome Research Institute and National Institute of Diabetes and Digestive and Kidney Diseases)</span></em></p>You are probably familiar with graphics depicting the double helix structure of DNA. But have you ever seen a single DNA molecule standing straight?David M. Gilbert, Professor of Molecular Biology, Florida State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/362502015-02-10T03:23:16Z2015-02-10T03:23:16ZWhy the causes of cancer are more than just random ‘bad luck’<figure><img src="https://images.theconversation.com/files/71552/original/image-20150210-24704-b63age.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Is cancer just a mathematical game of chance? </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/stuartpilbrow/2938100285">stuartpilbrow/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>What causes cancer? This deceptively simple question has a devilishly complex answer. So when US researchers proposed a relatively simple mathematical formula to explain a long-standing conundrum in cancer earlier this year, it was bound to get a lot of attention. </p>
<p>The study <a href="http://www.sciencemag.org/content/347/6217/78">published in the journal Science</a> suggested a correlation between the variation in cancer occurrence between different tissues and the number of stem cell divisions in each tissue. In other words, it said the tissues most vulnerable to cancer are those with the greatest number of stem cell divisions. </p>
<p>Most of the <a href="http://www.express.co.uk/life-style/health/549764/Study-reveals-cancer-down-to-just-sheer-bad-luck">reporting about the research</a> ran with the line that “cancer is all down to bad luck”, implying that developing the disease is out of our hands and that preventative efforts might be useless. But is that really the case?</p>
<p>Much of the misunderstanding seems to have arisen from the authors’ statement that a third of the variation in cancer risk among tissues is attributable to environmental or inherited factors, with the majority due to random mutations during DNA replication in normal cells. This statement about <em>relative</em> risk was overblown into blanket conclusions about the underlying causes of cancer.</p>
<h2>The wonder of replication</h2>
<p><a href="https://theconversation.com/explainer-what-is-cancer-1673">Cancer</a> emerges when one of the cells that make up your tissues (and organs) grows and divides without control, losing its specialised function and invading other tissue. This happens when normal control of cell growth and division is compromised through changes, or mutations, in your genome (the chemical instruction book for life). </p>
<p>Mutations lie at the heart of cancer biology.</p>
<p><a href="https://theconversation.com/an-insiders-account-of-the-human-genome-project-13040">The genome</a> is made from a chemical alphabet of just four letters (A,T,G, and C) “written” into DNA. It works like a kind of computer software for our cells, with strict instructions for growth and function. </p>
<p>Each of the 100 trillion cells in your body contains roughly six billion letters (called nucleotides) of this code, condensed into a thin strand of DNA about two metres long. To put this into perspective, if you stretched out all the DNA in a human body it would reach around the moon and back several times.</p>
<p>Every time a cell divides, the genome must be copied accurately and quickly. This synthesis of new DNA is called replication, and the numbers behind it are staggering. <a href="http://www.london-research-institute.org.uk/research/john-diffley">UK researcher John Diffley</a> has calculated that you will have synthesised the equivalent of a light-year of DNA (10 trillion kilometres) by the time you’re 50.</p>
<p>Words simply cannot do this amazing process justice, but this <a href="http://www.hhmi.org/biointeractive/dna-replication-advanced-detail">short video by award-winning animator Drew Berry</a> will blow your mind:</p>
<p></p>
<p>DNA replication has evolved to be incredibly efficient and reliable, but random mistakes (mutations) occasionally happen. Still, they occur at a rate of less than once per genome per cell division, thanks to some impressive molecular proofreading machines, which constantly survey the newly copied DNA and correct errors. </p>
<p>But with so many cells dividing so often, DNA replication still represents a major source of mutations. And every cell division increases the chance of accumulating mutations in important genes, increasing the likelihood of cancer.</p>
<h2>Other sources of mutation</h2>
<p>Mutations can take many forms and can emerge in a number of ways – not just through replication errors. We inherit between 50 and 100 mutations from our parents at birth, for instance, and any new or <em>de novo</em> mutations act on this inherited genetic background. </p>
<p>Even normal cellular metabolism damages DNA through the production of reactive oxygen. And, in a sinister twist, many of the inherited mutations that predispose people to cancer hit genes that control the DNA proofreading and repair systems (such as the <a href="http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA">breast cancer genes BRCA1 and BRCA2</a>). This has the effect of amplifying the rate of new mutations.</p>
<p>The other major causes of DNA mutation are lifestyle or environmental factors. We are exposed to a range of these in our everyday lives, such as <a href="https://theconversation.com/sun-damage-and-cancer-how-uv-radiation-affects-our-skin-34538">UV radiation from sunshine</a>, and chemicals including <a href="https://theconversation.com/health-harms-of-asbestos-wont-be-known-for-decades-14845">asbestos</a> or from <a href="https://theconversation.com/chemicals-in-cigarette-smoke-linked-to-lower-fertility-5375">smoking cigarettes</a>. </p>
<p>Lifestyle factors including <a href="https://theconversation.com/better-diet-exercise-could-prevent-43-000-cancers-and-save-674-million-5904">diet</a> and <a href="https://theconversation.com/health-check-does-alcohol-cause-cancer-22959">alcohol consumption</a> may also contribute. Some viruses and bacteria are known to cause DNA damage leading to cancer. They include the <a href="https://theconversation.com/four-things-you-should-know-about-hpv-vaccinations-15178">human papillomavirus (HPV) for cervical cancer</a> and <em>H. pylori</em> for gastric cancer.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Not off the hook: alcohol and diet can contribute to DNA mutations.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/calaveth/3862284313">Erik/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>Although these <a href="http://www.nature.com/nature/journal/v500/n7463/full/nature12477.html">different agents leave unique chemical signatures in the DNA</a>, they are still essentially random events. Random mutations are, in fact, the raw material driving evolution. And the processes of mutation and evolution are accelerated in cancer. Indeed, we are only now starting to understand the <a href="http://www.nejm.org/doi/full/10.1056/NEJMra1204892">importance of evolution in driving cancer</a> emergence and spread, as well as its resistance to therapy.</p>
<h2>Minimising risk</h2>
<p>Where does this leave the idea that cancer is all down to bad luck? Is modifying your lifestyle to minimise exposure to risk factors futile?</p>
<p>As usual, reality lies somewhere in the middle of competing narratives. Life is a kind of genetic gamble. We have to play the cards dealt us, but we can stack the odds in either direction by altering our exposure to environmental and lifestyle factors. Suggesting cancer is all down to bad luck dilutes the important message that risk can be modified by behaviour.</p>
<p>The cancer lexicon is littered with <a href="http://well.blogs.nytimes.com/2012/06/14/life-interrupted-feeling-guilty-about-cancer/?_r=0">notions of guilt</a> and blame. Death is often framed as “losing the battle with cancer”, for instance. And patients and their families are bombarded by gurus profiteering from various diet and lifestyle interventions. Their implicit messages can often leave people feeling that their cancer is all their own fault and wondering if there was something they could have done differently.</p>
<p>The fact remains that, in many cases, there isn’t.</p><img src="https://counter.theconversation.com/content/36250/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Darren Saunders receives funding from the NHMRC, Mostyn Family Foundation and Garvan Research Foundation</span></em></p>What causes cancer? This deceptively simple question has a devilishly complex answer. So when US researchers proposed a relatively simple mathematical formula to explain a long-standing conundrum in cancer…Darren Saunders, Laboratory Head, Garvan InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/201662013-12-02T06:25:47Z2013-12-02T06:25:47ZSelfish gene solves DNA replication puzzle<figure><img src="https://images.theconversation.com/files/36538/original/66qpkkrb-1385729269.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The Dead Sea reveals new growth strategy.</span> <span class="attribution"><span class="source">ilaufer</span></span></figcaption></figure><p>You were formed from a single cell. To build you, and then keep you alive, the DNA in your cells needs to undergo replication every day to duplicate your chromosomes before cell division. Decades of research have determined that DNA replication begins at specific locations on the chromosome. These sites are called replication origins. Bacteria have a single replication origin but more complex organisms, such as humans, need thousands of these start sites.</p>
<p>In a paper recently published in <a href="http://dx.doi.org/10.1038/nature12650">Nature</a>, our group at the University of Nottingham has demonstrated that not only are these start sites unnecessary, but that cells grow faster without them. This has implications for understanding the out-of-control DNA duplication seen in cancer cells.</p>
<p>Our research on DNA replication was carried out in the single-celled organism <em>Haloferax volcanii</em>, which is a member of the archaea. The tree of life is split into three groups: eukaryotes (including us), bacteria and archaea. Archaea are microbes best known for living in extreme conditions such as acid pools, hydrothermal vents and salt lakes. <em>H. volcanii</em> originates from the Dead Sea.</p>
<p>We chose <em>H. volcanii</em> because the enzymes that carry out DNA replication in archaea are similar to, but less complex than, those used in multi-cellular organisms. Therefore, understanding a key process such as genome duplication in archaea can inform us about the same process in humans.</p>
<p>We used a type of DNA sequencing to count DNA fragments in replicating cells. Any fragments present in two copies must have been duplicated, and will point to the location of replication origins. We were able to show that <em>H. volcanii</em> uses several origins to replicate its chromosome. But when all of these replication origins are removed, not only are the cells alive, but surprisingly they grow 7.5% faster.</p>
<p>Doing these experiments in human cells would have been impossible. When replication origins are eliminated from eukaryotes or bacteria, it prevents DNA replication and eventually leads to death. So how is <em>H. volcanii</em> able to survive? We found that cells without origins use an alternative method called recombination to begin DNA replication. Recombination is a form of DNA repair, it is normally used to mend breaks in the chromosome.</p>
<p>Why does this lead to faster growth? By using DNA sequencing, we showed that recombination is able to begin DNA replication at all locations on the chromosome with equal efficiency. In other words, it is not restricted to a limited number of sites such as replication origins, and this makes the process faster. But this poses a puzzle: if the alternative process using recombination is more efficient, then why have replication origins at all?</p>
<p>In our paper we suggest that replication origins in <em>H. volcanii</em> are an example of a selfish gene. Selfish genes need not offer any advantage to the host organism, they can even be detrimental to its fitness. But they increase their own gene frequency because they are duplicated along with the rest of the genome. In this case, the origin has hijacked the DNA replication machinery to ensure their own survival.</p>
<p>Why does this matter? The unusual mechanism of DNA replication we have discovered in <em>H. volcanii</em> has parallels with cancer. The organism has multiple copies of its genome and helps the organism survive without regulated DNA replication. Many cancer cells have mutations in the genes that control DNA replication, and multiply genome copies are a common feature of cancer cells. </p>
<p>Another consequence of unchecked DNA replication is that cancer cells grow faster than ordinary cells, which can lead to tumours spreading throughout the body. This accelerated growth is reminiscent of originless <em>H. volcanii</em>, which use alternative mechanisms of replication to outpace other cells.</p>
<p>Our work on a microbe from the Dead Sea has shown how surprising results can come from testing long-held assumptions in unusual organisms. But the work has given us more questions than answers. How exactly does this alternative mechanism of DNA replication work? Does <em>H. volcanii</em> use it all the time? How widespread in nature is this mechanism? Work on this process may contribute to our understanding of how cancer cells evade the normal checks on DNA replication.</p><img src="https://counter.theconversation.com/content/20166/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Michelle Hawkins has received funding from the BBSRC and the School of Biology, University of Nottingham</span></em></p><p class="fine-print"><em><span>Conrad Nieduszynski currently has funding from the BBSRC.</span></em></p><p class="fine-print"><em><span>Thorsten Allers has received funding from the Royal Society and the BBSRC.</span></em></p>You were formed from a single cell. To build you, and then keep you alive, the DNA in your cells needs to undergo replication every day to duplicate your chromosomes before cell division. Decades of research…Michelle Hawkins, Researcher in Biology , University of YorkConrad Nieduszynski, Lecturer in Genome Dynamics, University of NottinghamThorsten Allers, Lecturer in Archaeal Genome Biology, University of NottinghamLicensed as Creative Commons – attribution, no derivatives.