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Tangled yarn

Tangled yarn may be frustrating for a knitter, but tangled DNA can be deadly for a cell.

You have a lot of DNA in your cells, and we mean a lot.

Every cell packs around two metres of the stuff into a space smaller than the head of a pin, thanks to an incredible feat of biological engineering. But it’s not enough to just cram it in there, like the jumbled contents of an overstuffed suitcase. DNA needs to be used and therefore accessible.

Genes – the instructions encoded within our DNA – constantly need to be accessed and read, telling cells when and where to make all the molecules that are essential for life. And all the DNA in a cell has to be unwound and copied in readiness for it to divide to create two new cells.

Led by Dr Simon Boulton, who we recently profiled on the blog, scientists at our London Research Institute have now discovered that a molecule called RTEL1 plays a vital role in untangling DNA so it can be copied. They’ve also shown that faults in RTEL1 might be implicated in the development of several types of cancer, including lymphoma and brain tumours.

Let’s unravel these new results.

Introducing RTEL1

Our story centres on a molecule called RTEL1 or, to give it its full name, Regulator of Telomere Length 1. It was first discovered in 2004 by a team of Canadian researchers, who found that cells carrying a faulty version of the gene had unusually short telomeres – the structures that protect the ends of chromosomes (individual lengths of DNA), stopping them from unravelling or becoming damaged.

Problems with the telomeres can lead to cancer, as chromosomes get nibbled away from the ends inwards or fuse together, messing up crucial genes. It turns out that RTEL1 is a type of molecule known as a helicase, which helps to untwist DNA. RTEL1 unwinds the DNA in the telomeres so they can be copied correctly, making sure they stay the right length. But that’s not all it can do.

Skip forward four years to 2008, when Dr Boulton and his team published a paper showing that the version of RTEL1 in tiny roundworms is involved in protecting cells against DNA damage. Animal cells contain two copies of each chromosome, so cells will often repair damage to DNA on one chromosome by copying the appropriate code from the undamaged pair. Known to scientists as ‘homologous recombination’, it’s analogous to taking a photocopy of a page in a book to replace a damaged page in an identical volume.

But this process is risky and things can go awry. There’s a chance that the wrong DNA will be copied or that it will get hopelessly tangled and broken in the process. RTEL1 steps in and stops the copying process by unwinding the two chromosomes if something looks wrong, before any damage occurs.

Faults in RTEL1 have been implicated in an extremely rare genetic disease called Hoyeraal-Hreidarsson syndrome. Children born with the condition have multiple severe health problems, including a strong chance of developing cancer, and tend to die before their tenth birthday. Researchers have also discovered that variations in RTEL1 might be linked to an increased risk of glioma – the most common type of brain tumour.

So we know that RTEL1 helps cells to maintain their telomeres, and keeps a check on DNA repair by homologous recombination. Dr Boulton’s new paper, published in the journal Science, reveals yet another side to this molecular multi-tasker.

Copy and twist

New cells are created when one cell divides into two. This happens millions of times every single minute within the body, regenerating and repairing our skin, gut, blood and much more. To do this, all the DNA within a cell must be copied, so each ‘daughter’ receives an identical set of genes. But unravelling and copying two metres of twisted, tightly packed DNA is a complex job.

Making sure that this mess of biological string doesn’t get tangled up while being copied is a job for helicases, which are responsible for untangling and unwinding DNA. If helicases don’t do their jobs properly, cutter enzymes called nucleases step in and snip away at the mess, like a frustrated knitter giving up on carefully teasing a tangled ball of yarn apart and attacking it with the scissors.

Just as hacking at a ball of wool doesn’t do much for the quality of the resulting sweater or socks, cutting up DNA in order to untangle it is a dangerous business. There’s a good chance that it won’t be repaired correctly and neatly, running the risk of introducing critical errors in the genes that can lead to cancer.

Dr Boulton and his team found that RTEL1 can stick to a ring-shaped protein called PCNA, which plays a vital part in the DNA copying process. PCNA clips around a strand of DNA that needs to be copied and trundles along it, smoothing a path for the DNA duplication ‘machinery’ to follow. So the researchers wondered if RTEL1 might be helping PCNA out by untwisting the DNA to make sure that copying happens correctly.

Testing the untwister

To find out, the team focused on the specific part of RTEL1 that sticks to PCNA. They created a version of RTEL1 with alterations in this crucial region, meaning that while the whole protein could still work as a helicase, it could no longer cling onto PCNA.

Experiments with cells grown in the lab showed that, as expected, this modified version of RTEL1 no longer hung around with PCNA. The cells had high levels of damaged DNA, and didn’t copy their DNA or grow properly.

This suggests that RTEL1 is genuinely playing a part in the DNA copying process, and helping to protect against damage caused during duplication. There were also problems with the telomeres, although not as severe as those seen in cells completely lacking RTEL1, showing that the team of PCNA and RTEL1 is essential for some jobs at the telomeres but not others.

The scientists also noticed an intriguing effect on the way that the cells started copying their DNA. Usually, cells start to copy their DNA in a relatively small number of places, known as replication origins – eventually these join up as the whole genome is duplicated. But in cells in which RTEL1 and PCNA couldn’t work together, the researchers noticed an unusually high number of replication origins, suggesting that the cells are trying to copy their DNA but getting stuck – perhaps because their DNA is too tangled.

But to find out whether this lack of interaction was actually important in the development of cancer, the scientists had to turn to a real life scenario.

RTEL1 and raised cancer risk

Next, Dr Boulton and his team used genetic engineering techniques to create mice carrying the modified version of RTEL1 that can’t stick to PCNA. To increase the chances that they would see an effect on cancer risk they worked with animals that carried a fault in a gene called p53, which already have an increased chance of developing the disease. Unlike animals completely lacking RTEL1, which die in the womb, these mice appear to be fine and grow into adults. But there are problems.

The scientists found that animals carrying the faulty version of RTEL1 developed cancer quicker than those with the regular version, including cancer of the lymphatic system (lymphoma), soft tissue cancers (sarcomas) and teratoma – an unusual cancer that tends to start in the ovary or testicle.  Some of the mice developed medulloblastoma, which is the most common type of brain cancer in children.

This last discovery is important because, as we mentioned, faults in RTEL1 have already been implicated in people with glioma brain tumours, although it’s not entirely clear why these animals developed medulloblastoma rather than glioma. It could be due to underlying differences between humans and mice, and it’s certainly something that needs to be explored further.

Where now?

These new results cement the importance of RTEL1 in a range of roles within the cell – at the telomere, during DNA repair, and now in DNA copying too. The discovery that interfering with RTEL1’s ability to help with DNA duplication raises cancer risk is a significant new discovery. It tells us that the molecule normally acts to keep cancer under control, acting as a tumour suppressor.

More research now needs to be done to unpick the links between RTEL1 and certain types of cancer – notably brain tumours, where improvements in research and treatment are urgently needed. And while these findings advance our understanding of the basic biology that underpins cancer, it’s too early to turn them directly into new therapies for patients.

Dr Boulton has an impressive track record in making important discoveries that deepen our knowledge about the fundamental processes involved in healthy and cancerous cells. This kind of work is the cornerstone of virtually all new developments in cancer diagnosis and treatment, so we look forward to seeing the next chapter in the story of RTEL1.

Kat

Reference:

Vannier J.B. et al. (2013). RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication, Science, 342 (6155) 239-242. DOI:

Images courtesy of Wikimedia Commons.

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