This sticky end is a clue to cancer’s causes

How do healthy cells turn cancerous? Their  DNA gradually accumulates errors. Most of these errors aren’t important, but occasionally they stop the cell from working properly. They might cause a cell to grow out of control – and this can lead to cancer.

Myelodysplastic syndromes, or MDS, are a range of blood disorders caused by such errors in the genes. Some types of MDS are relatively mild, but about a third go on to become acute myeloid leukaemia (AML). Thanks to research on MDS we understand its causes a lot better than we did ten or fifteen years ago.

My lab recently published a paper describing three cases of poor prognosis MDS and one case of AML with unusual but remarkably similar changes to the DNA. This complicated structure could not have been predicted by the standard methods of analysing cancer DNA or chromosomes. These features showed us the likely steps that led to these diseases.

Each long string of DNA is folded up neatly to make a chromosome. This is a Claymation that shows how Barbara McClintock’s classic breakage-fusion-bridge cycle causes chromosome abnormalities. The video shows one way that chromosomes (packages of DNA) can become disorganised.

The  telomeres (that cap and protect the ends of the chromosomes) are shown falling off, making sticky chromosome ends which join together (see NOTE 2). It’s well accepted that these changes greatly increase the chance of cancerous gene changes. This process has reproduced many, many times in the lab. The problem is that it’s not often been demonstrated in actual cancers. But we did that.

Sometimes only part of the telomere erodes away – enough is lost that it no longer protects the chromosomes from sticking together. But there can be enough telomere DNA left to be a molecular signature of the telomere.

The arrow points to green dots in the middle of a chromosome. This is the left-over telomere signature that tells us that this abnormal chromosome was made by the joining together of sticky chromosome ends that had their telomeres eroded away. The other green dots are at the chromosome ends. The left and right photos show the same cell but in the right one the abnormal chromosome is identified by its red and blue label.

The arrow points to green dots in the middle of a chromosome. This is the left-over telomere signature that tells us that this abnormal chromosome was made by the joining together of sticky chromosome ends that had their telomeres eroded away. The other green dots are at the chromosome ends. The left and right photos show the same cell but in the right one the abnormal chromosome is identified by its red and blue label.

In our four cases we found that there was a small but non-functional piece of telomere DNA left behind where the two chromosomes joined. Because the telomeres didn’t function, the two chromosome ends could stick together. These caused breakage-fusion-bridge events that caused a protective tumour suppressor gene to be lost, and may have also caused cancer-causing genes to multiply.

MDS and AML have similar genetic causes, so if we learn about the causes of one of them it can help us understand the other. This is often the case with cancer research in a broader sense – if we understand the basic mechanisms in one cancer it can help us understand the mechanisms at work in other cancers better. Telomere fusion could potentially play a role in any cancer, so our MDS research is relevant to cancer research in general.



The paper: The dicentric chromosome dic(20;22) is a recurrent abnormality in myelodysplastic syndromes and is a product of telomere fusion. Ruth MacKinnon, Hendrika Duivenvoorden, Lynda Campbell and Meaghan Wall, 2016. Cytogenetic and Genome Research 150(3-4):262-272
The gene errors discussed here usually occur in the body cells rather than the reproductive cells, so they’re not inherited.
For simplicity the Claymation shows telomere fusion in chromosomes that are dividing.  In fact it probably occurs when the DNA is unravelled in the interphase nucleus.

This is cross-posted from

How some rediscovered 75-year-old research on maize helps us understand cancer

Barbara McClintock published a paper describing the breakage-fusion-bridge (BFB) cycle in 1939. She studied the genetics of maize, and many of her ideas were well before their time. Like many such profound leaps in thinking, the BFB cycle took a long time to catch on. She wrote in 1973, “I stopped publishing detailed reports long ago when I realized, and acutely, the extent of disinterest and lack of confidence in the conclusions I was drawing …One must await the right time for conceptual change.” Her work was appreciated much later and she was awarded a Nobel Prize in 1983 for her discovery of “jumping genes“.

Fast forward 75 years and we have an unexpected benefit of this seemingly obscure plant research. It can help us understand some of the mechanisms involved in cancer. The rediscovered breakage-fusion-bridge cycle can make cancer very aggressive, and it may be much more common than we think. Centromeres (see below) are the key to the BFB cycle, but  centromeres are largely overlooked, both in research and diagnostics.

This is how it works.

The breakage-fusion-bridge cycle is one way that chromosome division can go wrong. Very wrong, in the sense that it can cause the chromosomes to keep changing, and this can cause cancer. I’ve put together this animation, which illustrates the breakage-fusion-bridge cycle. There’s a summary of normal chromosome division on my blog,

A human chromosome with two centromeres is abnormal. One way this can happen is when the telomeres become degraded (see a previous post). Chromosomes with two centromeres are not unusual in cancer cells. In fact they’re probably a lot more common than we think, because in both research and diagnostic labs the centromeres are usually not looked at.

To recap, a normal chromosome has one centromere. Before the chromosome divides, the two identical halves (chromatids) are held together at the centromere. When the chromosome divides the centromere splits into two halves, the chromatids become the new chromosomes, and the centromeres take the two new chromosomes in different directions into the two new daughter cells.

So what happens if there are two centromeres? If they’re both aligned so that they head in the same direction it’s not a problem – together they take a complete new chromosome with them. The closer the centromeres are together the more likely this is.

Now follow the pictures and their captions. These describe chromosome division in an abnormal chromosome with two centromeres. In particular, follow the yellow dots.

A twist between the two centromeres when the chromosomes align ready for chromosome division.
If the two centromeres on a chromosome go in the same direction there’s no problem. But if there’s a twist between the two centromeres when the chromosomes align ready for chromosome division….
....then, when the two halves of each centromere separate they head off in different directions.
….then, when the two halves of each centromere separate they go in opposite directions. We have a “bridge” spanning the gap between the two centromeres.
The bit of chromosome between them gets stretched and can break.
The bridge is stretched and can break.
The broken chromosomes in the new cell join together - the top daughter cell gets an extra copy of the yellow gene. The bottom cell loses this copy of yellow gene.
The broken chromosomes in the new cell join together – the top daughter cell gets an extra copy of the yellow gene. The bottom cell loses this copy of the yellow gene.
The new chromosome copies itself to make two equal halves.
The new chromosome copies itself to make two identical chromatids.
If this process repeats..
If this process repeats..
Fusion of the broken bits of chromosome in the top cell.
Fusion of the broken pieces creates a chromosome with four copies of the yellow gene.
After replication - the new chromosome with four copies of the yellow gene courtesy of the breakage-fusion-bridge cycle.
After replication.

If the yellow gene in the pictures is a cancer gene (“oncogene”) the cell with extra copies might grow and multiply faster than its neighbors. We call this natural selection – the cells that can grow faster than their neighbors become more common, which means the genetic change causing that is undergoing “positive selection”. Yes, the cells in our body can evolve and we know this best as cancer.

All this change happens between the two centromeres where the bridge forms. So if we find a chromosome with this type of change on one side of the centromere only, it’s a clue that this might have been caused by the breakage-fusion-bridge cycle.

Many (perhaps most) images demonstrating the BFB cycle show a different version – where the abnormal chromosome is created by breakage and joining together of the two chromatids of one chromosome. Check this out on Google Images (search for breakage-fusion-bridge). But I think the version I’ve shown here – where two different chromosomes join – is probably more common. It’s the more common version in my experience with acute myeloid leukemia.


(This is a modified version of a post in my blog.)

Further Reading:

B. McClintock 1939. The Behavior in Successive Nuclear Divisions of a Chromosome Broken at Meiosis. Proc Natl Acad Sci U S A. 1939 August; 25(8): 405–416.

M. Kinsella and V. Bafna 2012. Combinatorics of the Breakage-Fusion-Bridge Mechanism. J Comput Biol. 2012 June; 19(6): 662–678.

R. MacKinnon and L. Campbell 2011. The Role of Dicentric Chromosome Formation and Secondary Centromere Deletion in the Evolution of Myeloid Malignancy. Genetics Research InternationalVolume 2011 (2011), Article ID 643628.

Eternal youth, cancer and telomeres

This is an edited version of a post in my blog – The back-story is that I was approached by a national current affairs program to do an interview on telomeres. Being a cancer researcher I thought the story might be about cancer. It turned out the focus was on cosmetics. How so? Having done some extra background reading I’ve tried to put together a balanced view of telomeres’ role in cancer and aging and how they might be manipulated to cure diseases caused by telomeres that are too short or too long.

Genes are strung together on a long molecule called DNA. Together the genes make up the instruction manual that controls the workings of each cell as well as the way the cells co-ordinate with each other. (Have a look at Abby Buchwalter’s post for a good description of a cell in simple language.) There are 46 of these long strings of DNA in each of our cells (with a few exceptions). When a cell finishes growing and divides to become two cells, these 46 strings of genes fold up to become recognizable chromosomes – we can see these with a microscope.

At each end of a chromosome there’s a short stretch of DNA called the telomere. This caps the chromosome to protect it from eroding or from sticking to other chromosomes. Our telomeres start out at a set length in a fertilized egg. A tiny part of the telomere is lost every time a cell divides, so our telomeres get shorter as we grow older. Other factors, such as extreme psychological stress, and toxins such as chemotherapy, are also thought to cause telomere shortening.

The green spots mark the telomeres on the chromosomes from a leukemia cell. Can you spot the two abnormal “ring” chromosomes? Hint: a ring has no end. (The solution will be posted at shortly.)

When telomeres get too short, the chromosomes can join together to become one abnormal chromosome. Cells with dangerously short telomeres usually self-destruct. But if the cell escapes self-destruction, these joined-together chromosomes can be unstable and risk making the cell cancerous – outgrowing its neighbors and dividing indefinitely.

Click here to see a telomere fusion animation.

Here’s the paradox – short telomeres can cause cancer, but cancers re-lengthen their telomeres to become immortal.

Cancers usually lengthen their telomeres by activating an enzyme (a protein which causes chemical reactions) called telomerase. It’s been suggested that shortening the telomeres of cancer could be an effective treatment. Some researchers are trying to do this by destroying the telomerase in cancer cells.

Besides cancer, short telomeres are thought to cause other diseases that we associate with aging, such as osteoarthritis, diabetes, and cardiovascular disease. Some people are born with short telomeres – and they can get a similar range of diseases. In one interesting study, mice without telomerase aged prematurely, but they regained their health when this enzyme was replaced. So there are also researchers looking at the possibility of using telomerase to cure diseases that are associated with short telomeres, or to reverse the effects of aging. TA-65® is a chemical that can activate telomerase. It’s already available in some cosmetics, where it’s promoted as an anti-aging treatment. This same chemical is being tested for use as a treatment for diseases linked to aging and short telomeres.

Drugs that lengthen or shorten telomeres will need to be tested carefully to make sure they don’t have unwanted side effects, before they can be used for treating medical conditions or as an anti-aging treatment. In particular, because telomere lengthening allows cells with abnormal chromosomes to become immortal, artificially lengthening telomeres could be a cancer risk. There’s debate about this, but obviously it would need to be pretty clear that the risk is negligible before telomere lengthening drugs are used as an anti-aging strategy. TA-65® is allowed in cosmetics because they aren’t governed by the same regulations as drugs.

There’s a strong link between short telomeres and stress-related diseases. There’s also evidence that drug-free measures like reducing stress, exercise and an improved diet, can stop or even reverse premature telomere shortening. These are safe and available now.

Telomeres were originally a niche specialty area of basic science with no obvious health implications. Telomere research now gives some hope to people with cancer and other diseases, and even people who are hoping to find the key to eternal youth.


C. Buseman 2012. Is telomerase a viable target in cancer? Mutation Research 730:90-97

E. Callaway 2010. Telomerase reverses ageing process. Dramatic rejuvenation of prematurely aged mice hints at potential therapy. Nature 28th November 2010 (published online).

B. de Jesus et al. 2011. Aging by telomere loss can be reversed. Cell Stem Cell 8:3

C. Harley et al. 2011. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Research 14:45-56.

R. MacKinnon and L. Campbell 2011. The role of dicentric chromosome formation and secondary centromere deletion in the evolution of myeloid malignancy. Genetics Research International Article ID 643628

T. Morin. A balanced article on telomeres in Dayspa Magazine online.


E. Blackburn and E. Epel 2012. Too toxic to ignore. Nature 490:169-171 (about stress, disease and telomere shortening). Note, Elizabeth Blackburn is Australia’s only female Nobel Prize winner (in science at least) – she shared the prize for Physiology or Medicine in 2009 for her discovery of telomeres.

B. de Jesus et al. 2013. Telomerase at the intersection of cancer and aging. Trends in Genetics (available online 19th July 2013)