Biologists reported today in Nature that they have identified two pathways through which chromosomes are rearranged in mammalian cells. These types of changes are associated with some cancers and inherited disorders in people.
"Our finding provides a target to prevent these rearrangements, so we could conceivably prevent cancer in some high-risk people," said senior author Edward P. (Paul) Hasty, D.V.M., of the School of Medicine at The University of Texas Health Science Center at San Antonio. Partial funding came from the Cancer Therapy & Research Center at the UT Health Science Center San Antonio.
The two pathways rearrange chromosomes by recombining DNA repeats that are naturally found in the genome, Dr. Hasty said. DNA, the chemical substance of genes, denatures and replicates during cell division and other processes. Repeats are sequences of DNA that are duplicated.
Both pathways are important for the synthesis of DNA. "Therefore, we propose that chromosomal rearrangements occur as DNA is being synthesized," Dr. Hasty said.
The experiments were conducted with mouse embryonic stem cells grown in tissue culture. The team measured the incidence of DNA repeats recombining in normal cells. This is called "repeat fusion." The scientists then looked for incidence of repeat fusion in cells affected by several genetic mutations. This analysis identified the two pathways and showed large, complicated rearrangements that involved DNA repeats on multiple chromosomes.
During cell division, DNA is coiled into pairs of threadlike structures called the chromosomes. Each human cell has 22 numbered pairs of chromosomes called autosomes. The sex chromosomes are the 23rd pair in cells and determine a person's gender. Females have two X chromosomes, while males have an X and a Y chromosome.
"We hope the new findings will help us better understand the mechanisms that cause chromosomal instability, which causes some cancers in people," Dr. Hasty said.
At the Health Science Center, Dr. Hasty is a professor in the Department of Molecular Medicine, has a laboratory at the UT Institute of Biotechnology, and is a faculty member of the Barshop Institute for Longevity and Aging Studies.
This work was supported by the National Institutes of Health (1 RO1 CA123203-01A1 to Drs. Paul Hasty and Cristina Montagna, 2P01AG017242-12 to Dr. Hasty, P30CA013330 to Dr. Montagna) and with support from the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio (P30 CA054174).
Two Replication Fork Maintenance Pathways Fuse Inverted Repeats to Rearrange Chromosomes
Lingchuan Hu1, Tae Moon Kim1, Mi Young Son1, Sung-A Kim1, Cory L. Holland1, Satoshi Tateishi2, Dong Hyun Kim1, P. Renee Yew1, Cristina Montagna3, Lavinia C. Dumitrache1,4, and Paul Hasty1
1Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245-3207, USA
2Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1 Kumamoto 860-0811 Japan
3Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. 10461
4Current address: Department of Genetics & Tumor Cell Biology, M/S 331, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tenn. 38105
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The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio is one of the elite academic cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center, and is one of only four in Texas. A leader in developing new drugs to treat cancer, the CTRC Institute for Drug Development (IDD) conducts one of the largest oncology Phase I clinical drug programs in the world, and participates in development of cancer drugs approved by the U.S. Food & Drug Administration. For more information, visit http://www.ctrc.net.
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