Stress strikes cytogenetics

Cellular stress during replication induces many small deletions and duplications in the genome, adding fuel for human diversity and disease, researchers reported today (Nov. 13) at the __American Society of Human Genetics__ linkurl:meeting;www.ashg.org/2008meeting/ in Philadelphia. Replication stress is known to be hazardous for the cell, and is thought to contribute to ageing and cancer. But exactly how stress causes DNA damage has remained unclear. Last year, a team led by linkurl:Thomas Glover,;http://www.hg.med.umich.edu/facultyprofile.php?id=7 a human geneticist at the University of Michigan, Ann Arbor, showed that human-mouse hybrid cells exposed to linkurl:aphidicolin;http://en.wikipedia.org/wiki/Aphidicolin -- an antibiotic that inhibits DNA polymerase and induces mitotic stress -- led to a high frequency of submicroscopic deletions at a particular genomic site with elevated susceptibility to DNA damage (__PNAS__, 105: 246-251, 2007). Now, Glover's team exposed linkurl:human fibroblasts;http://www.the-scientist.com/article/display/54683/ to the same stressful conditions, and compared the stressed out cells with their normal counterparts using array-based linkurl:comparative genomic hybridization.;http://www.the-scientist.com/article/display/53607/ Their results revealed a suite of sequence copy number changes -- deletions and duplications -- between the stressed sample and control DNA. They found that eight of their 14 stressed cell populations had at least one copy number change, compared to only one of 11 control populations. On average, each stressed cell population had 2.2 copy number changes after three days of aphidicolin-treatment -- about 10 times more changes than the control -- with no apparent patterning between chromosomes. "Numbers of deletions and duplications are just scattered across the genome," Martin Arlt, the study's lead author, said in a presentation. The deletions varied from 25 to around 1,300 kilobases, while the duplications were slightly larger, ranging from 143 to around 2,800 kilobases. In one instance, the researchers observed the same deletion in two independent cell lines, indicating that there might be a predictable pathway to stress-induced DNA damage. Glover's team sequenced the deletions' breakpoint junctions, and discovered that they were all characterized by short equivalent DNA sequences called microhomologies. This pattern is consistent with a particular form of DNA repair that uses microhomologies to mend DNA damage, known as linkurl:non-homologous end joining,;http://www.the-scientist.com/article/display/20076/ rather than other genetic fix-it methods that rely on matching DNA templates, the researchers concluded. Since the observed deletions and duplications closely resembled linkurl:copy number variants;http://www.the-scientist.com/article/display/54856/ seen in screens of human diversity, as well as spontaneous DNA changes implicated in diseases such as cancer, stress during cell division is likely a major contributor to both normal and aberrant genomic copy number changes, Arlt said.

Stress strikes cytogenetics

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