They are the Robinson Crusoes of the intracellular world: lone chromosomes, whole and hardy, stranded outside the nucleus where their fellow chromosomes reside. Such castaways, each confined to its own ?micronucleus,? are often found in cancer cells, but scientists haven?t known what role, if any, they play in the cancer process.
In a paper published online January 16 in Nature, Dana?Farber researchers describe a mechanism in which micronuclei ?disrupt the chromosomes within them and produce cancer-causing gene mutations. The findings may point to a vulnerability in cancer cells that could be attacked by new therapies.
The pulverized chromosome appears in red amid the normal chromosomes in white. Image courtesy of Pellman lab
?The most common genetic change in cancer is the presence of an incorrect number of intact chromosomes within cancer cells?a condition known as aneuploidy,? said senior author David Pellman, the Margaret M. Dyson Professor of Pediatric Oncology at Dana?Farber and Harvard Medical School professor of cell biology. ?How aneuploidy might trigger tumors, however, has been hard to pin down. In contrast, it?s well known that broken chromosomes and damaged DNA alters cancer genes in ways that spur runaway cell division.
?Our study shows one possible chain of events by which aneuploidy?and specifically ?exiled? chromosomes?could lead to cancer-causing mutations and has implications for cancer prevention and treatment.?
In normal division, a cell duplicates its chromosomes and dispatches them to the newly forming daughter cells: the original set to one daughter, the twin set to the other. For a variety of reasons, the chromosomes sometimes aren?t allocated evenly; one daughter receives an extra one, the other is short one. Unlike the rest of the chromosomes, these stragglers sometimes don?t make it to the nucleus. Instead, they become wrapped in their own membrane and form a micronucleus that exists separately in the cell.
Pellman?s research team found that a chromosome that becomes marooned in a micronucleus undergoes inefficient duplication that is out of sync with that of the cell?s other chromosomes. This double whammy results in damage to the chromosome, including the degree of breakage that, in previous research ?into aneuploidy, has been found in cancer cells generated from cells with micronuclei.
The team also found that damage to these chromosomes was so extensive, they appeared to be smashed to bits, a condition that linked the findings to those from studies that describes the recently discovered phenomenon called chromothripsis. In cancer cells exhibiting chromothripsis, ?one chromosome of the cell shows massive amounts of breakage and rearrangement, while the remainder of the cell?s genome remains largely intact. In addition, the team found that a third of the time, these pulverized bits are neither discarded nor digested by the cell. Instead they are donated to one of the daughter cells during cell division. The damaged chromosomes, therefore, could be incorporated into the cell?s genome and provide a potential cancer-causing mutations.
?Our findings suggest that whole-chromosome aneuploidy might promote cancer in a very similar way to other kinds of genomic alterations,? said Pellman. ?The key event may be mutations in oncogenes and tumor suppressors. This mechanism may also explain how cancer cells acquire more than one such mutation at a time.
?Although chromothripsis occurs in only a few percentage of human cancers, our research suggests? it represents an extreme example of chromosome damage that could be much more common,? added Pellman. ?Accelerating this process in cancer cells by generating so many mutations that the cells die may offer a strategy for new therapies against certain tumors.?
Originally published by Dana?Farber Cancer Institute.
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