Archives for posts with tag: Chromatid

Barbara McClintock published a paper describing the breakage-fusion-bridge (BFB) cycle in 1939. 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“.

A few weeks back I introduced this post by describing normal chromosome division. This time we’ll look at the breakage-fusion-bridge cycle. This is one way chromosome division can go wrong. Very wrong, in the sense that it can cause the chromosomes to keep changing, and this can cause cancer.

A human chromosome with two centromeres is abnormal. 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. Especially 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 equal halves.

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 neighbours. We call this natural selection – the cells that can grow faster than their neighbours 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.

These are modelling clay images from my breakage-fusion-bridge claymation. They’re a bit rough but I hope it helps you understand what happens. Many, perhaps most, images demonstrating the BFB cycle show a different version – where the abnormal chromosome is created by two chromatids of one chromosome breaking and joining together. Most examples don’t show the version I’ve presented – where two different chromosomes have joined together. Check this out on Google Images (search for breakage-fusion-bridge).

Here’s the answer to the quiz from the telomere post. The arrows point to the ring chromosomes. Being rings they have no ends, so no telomeres.

answer to ring chr

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.

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What makes a cell become cancerous?

This can happen if the chromosomes are incorrectly distributed to a new cell. The cell could get too many copies of a cancer-promoting gene, or too few copies of a cancer-protecting gene.

The breakage-fusion-bridge cycle is one way that this can happen. This  week I was asked to provide a cartoon showing the breakage-fusion-bridge cycle and how it relates to a chromosome abnormality I was describing.

By lucky coincidence my colleague Lan Ta just this week published a paper with a neat breakage-fusion-bridge cartoon that was put together by Bruce Mercer. As well as being a scientist, Bruce is a graphic artist – a very handy combination. So I was trying to draw the modified cartoon for Bruce in two dimensions, without much success. Then modelling clay came to the rescue and I was able to show him what I meant.

So I would like to share the 3D modelling clay version, but before we look at the breakage-fusion-bridge cycle, which is an abnormal pattern of chromosome division, we had better look at normal chromosome division (or mitosis).

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These are chromosomes in modelling clay. There are 23 pairs of chromosomes in a human cell but we will follow 3 chromosomes for simplicity.  The chromosomes only take on a recognisable shape when the cell is ready to divide. Each chromosome is made of two halves called chromatids, which are identical. These are held together at the centromere.

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In a cell the chromosomes are usually not recognisable – the DNA is unravelled in the nucleus. In a growing cell each unravelled  chromosome is producing a copy of itself so that there will be a chromosome for each of the two new daughter cells when the cell divides, or reproduces itself.

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After the chromosomes take shape they line up together (at the metaphase plate) between two ends, or poles, of the cell. The centromere has another very important function in cell division. It attaches to fine fibres (microtubules) which stretch between the poles.

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The two halves of the centromere separate and each draws its chromatid (which is now a new daughter chromosome) along these microtubules.

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So when the cell divides in two to make two new cells, each chromatid becomes a chromosome in one of the new cells.

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Cell division complete, the chromosomes unravel and copy themselves again ready for the next cell division.

This process happens successfully millions of times every day to create new cells in our bodies – amazing.