Chromothripsis, or ‘chromosome shattering’, is a mutational process in which large stretches of a chromosome undergo massive rearrangements in a single, catastrophic event. The chromosome region fragments into smaller pieces, re-joins, and rearranges, leading to a new genome configuration.
Understanding chromothripsis is essential for shedding light on the processes happening inside the cell and at a genomic level, when cancer arises.
A Nature paper from EMBL’s European Bioinformatics Institute (EMBL-EBI) and the University of Texas Southwestern Medical Center revealed how DNA fragments resulting from chromothripsis undergo complex rearrangements, which get passed on during cell division. In cancer, this is commonly associated with loss of DNA. However, in certain cases, such as congenital disorders and some tumours, chromothripsis leads to shuffling of the genome with only limited DNA loss. This suggests that there is a mechanism that somehow tethers DNA fragments together. This paper has elucidated what that mechanism is.
“Chromothripsis is a complex process that researchers have been gradually unpicking for over a decade,” said Isidro Cortes-Ciriano, Group Leader at EMBL-EBI and co-senior author of the study. “This new paper sheds light on the molecular mechanisms whereby DNA fragments arising from the fragmentation of chromosomes are inherited together by a single daughter cell to cause a particular type of chromothripsis characterised by shattering of the chromosomes but without DNA loss. This has been observed in some tumours and in the germline.
“This is basic biology that has key implications for how DNA mutations caused by chromothripsis happen in cancer and in the germline, and will help us interpret cancer genome sequencing data better.”
Chromosomes are bundles of tightly-coiled DNA located within the nucleus of almost every cell in our body. Each cell in humans has 23 pairs of chromosomes. Source: YourGenome
Chromothripsis was discovered in 2011 by researchers at the Wellcome Sanger Institute. By looking at the genomes of some cancer patients, they managed to spot clusters of DNA that had been rearranged, with some DNA getting lost in the process. This is similar to cutting a piece of string into tiny pieces, then rearranging them in a random order with some pieces getting lost in the process.
Years later, researchers discovered a surprising fact: in some cases chromothripsis could happen without the loss of DNA. This was observed in people with congenital disorders – meaning structural anomalies that occur before birth, commonly referred to as ‘birth defects’ – as well as in lung cancer patients, especially those who never smoked.
Researchers then concluded that there must be a spectrum of chromothripsis diversity: both with loss of DNA, and without loss of DNA.
In recent years, cell biologists have validated two ways in which chromothripsis happens in the cell. One way is when a chromosome loses a telomere, and it fuses to another chromosome during replication. This results in a chromosome with two ‘centromeres’. During cell division, the chromosome in question gets pulled in two directions, creating a kind of ‘bridge’, which can result in chromothripsis.
Another way in which chromothripsis happens is when a chromosome ‘lags behind’ during cell division, and fails to become incorporated into the cell nucleus. Instead, a nuclear envelope forms around them, in turn becoming small nuclei themselves. This means that if you look at the cell under a microscope, you will see the main cell nucleus, and alongside it a smaller nucleus. In these so-called ‘micronuclei’, DNA replication and repair don’t work properly, which means that if a chromosome ends up in a micronucleus, chromothripsis is more likely to happen.
Surprisingly, when chromothripsis takes place in a micronucleus, the resulting DNA fragments remain clustered, rather than being randomly distributed in the cell. A new question then arises about how DNA fragments are clustered together after fragmentation.
Telomeres are distinctive structures found at the ends of chromosomes. They consist of the same short DNA sequence repeated over and over again. Each time a cell divides, the telomeres become shorter. Eventually, they become so short that the cell can no longer divide and it dies.
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Using cell biology experiments and genome analysis, researchers have now discovered the mechanism by which the DNA fragments resulting from the fragmentation of a chromosome in a micronucleus stay together, thus providing a molecular explanation to the diversity of chromothripsis patterns observed in humans. They have found that the CIP2A-TOPBP1 protein complex is responsible for ‘glueing’ DNA fragments together so they can all be inherited by a single daughter cell.
“We were surprised to see that the chromosome fragments from micronuclei stuck together during cell division,” explained Peter Ly, Assistant Professor at the University of Texas Southwestern Medical Center and co-senior author of the study. “The expectation was that these DNA fragments would spread like shards of glass when something shatters, but our work has shown how and why they cluster together.”
“Our experiments pointed to the CIP2A-TOPBP1 protein complex as the mechanism sticking DNA fragments together, in turn preventing the loss of DNA pieces from chromothripsis” said Yu-Fen Lin, Senior Research Scientist at the University of Texas Southwestern Medical Center and first author of the study.
The cell biology work done at the University of Texas Southwestern Medical Center was complemented by in-depth analysis of whole genome data from the Pan-Cancer Whole Genome Analysis project. “Because for years, the criteria for chromothripsis were very strict, a lot of cases were missed,” explained Jose Espejo Valle-Inclan, Postdoctoral Fellow at EMBL-EBI. “Our analysis has found that chromothripsis without DNA loss occurs in about 5% of pan-cancer genomes, and the spectrum of complex rearrangements is more intricate than previously thought. These insights will hopefully support future cancer research.”
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