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Study uncovers new information on genomic instability

Date:
May 13, 2015
Source:
SUNY Upstate Medical University
Summary:
Researchers have mapped chromosome breaks in a model organism, and by doing so, have discovered new information as to how and where chromosome fragile sites can occur in human DNA. Their findings offer a better understanding of the mechanisms of chromosome fragile sites and could lead to a breakthrough in identifying new cancer-associated genes.
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Using a novel method they developed to map chromosome breaks in a model organism, the budding yeast, Wenyi Feng, Ph.D., of Upstate Medical University and her colleagues have discovered new information as to how and where chromosome fragile sites can occur in human DNA. These sites are frequently observed in cancer cells and are responsible for causing genomic rearrangements. Their findings offer a better understanding of the mechanisms of chromosome fragile sites and could lead to a breakthrough in identifying new cancer-associated genes.

The study was recently published in Genome Research. Feng, assistant professor in the Department of Biochemistry and Molecular Biology at Upstate, was joined in the study by Elizabeth A. Hoffman, Andrew McCulley, Brian Haarer, Ph.D, and Remigiusz Arnak, Ph.D.

Chromosome fragile sites are regions of DNA double strand breaks on human chromosomes. Feng says that the mechanism that causes these sites to occur is, to date, elusive. She adds that it is also unclear why distinct patterns of these sites are observed in different cell types and under different drug treatments.

She and her team developed the method Break-seq to test their hypothesis that chromosome fragile sites result from collisions between drug-induced unstable DNA replication and untimely gene transcription. This phenomenon could result in breakage in the human genome, and when a breakage impacts important genes, such as tumor suppressors, it could lead to cancer development. Break-seq combines an existing double strand break labeling system the researchers had used in an earlier study with next generation sequencing to map chromosome breaks with improved sensitivity and resolution.

"Using the anti-cancer drug and a replication inhibitor, hydroxyurea, in the model organism Saccharomyces cerevisiae, we observed that double strand breaks preferentially occurred at hydroxyurea-induced genes," said Feng. "This gave us evidence that, while anti-cancer drugs are effective in preventing tumor cells from replicating, they can also alter gene expression simultaneously as they inhibit DNA replication, a phenomenon that has not been investigated widely," she said.

Feng said that breakage patterns at different subsets of the hydroxyurea-induced genes were also observed in wild type cells and checkpoint-deficient mutant cells with unstable replication forks. "This is because while both cell types show hydroxyurea-induced gene expression, collision with replication occurs differentially because replication forks have progressed to different extent in these cells," said Feng.

She and her colleagues propose that other replication inhibitors to fight cancer will also produce unique double strand break profiles, as gene expression patterns would dictate the locations of replication-transcription conflicts.

"We are now investigating chromosome fragile site formation in various human cell lines, including the chronic myeloid leukemia and Fragile X cells," said Feng. "Our work will help us understand the underlying mechanisms and etiology for these debilitating human diseases."


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Materials provided by SUNY Upstate Medical University. Note: Content may be edited for style and length.


Journal Reference:

  1. Elizabeth A. Hoffman, Andrew McCulley, Brian Haarer, Remigiusz Arnak, Wenyi Feng. Break-seq reveals hydroxyurea-induced chromosome fragility as a result of unscheduled conflict between DNA replication and transcription. Genome Research, 2015; 25 (3): 402 DOI: 10.1101/gr.180497.114

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SUNY Upstate Medical University. "Study uncovers new information on genomic instability." ScienceDaily. ScienceDaily, 13 May 2015. <www.sciencedaily.com/releases/2015/05/150513145516.htm>.
SUNY Upstate Medical University. (2015, May 13). Study uncovers new information on genomic instability. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2015/05/150513145516.htm
SUNY Upstate Medical University. "Study uncovers new information on genomic instability." ScienceDaily. www.sciencedaily.com/releases/2015/05/150513145516.htm (accessed May 23, 2017).

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