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Cell Survival Depends on Chromosome Integrity

Johns Hopkins researchers have discovered protein machinery important for cells to keep chromosomes intact. Without such proteins, their experiments show that //yeast cells experience broken chromosomes and DNA damage that in human cells are well known to lead to cancer.

“Maintaining genome integrity is crucial for cell survival,” says Jef Boeke, Ph.D., Sc.D., the report’s senior author, a professor of molecular biology and genetics and co-director of the High Throughput Biology Center of the Institute for Basic Biomedical Sciences at Hopkins. The report will appear online July 6 in Current Biology.

Boeke and colleagues show that removing from yeast cells two proteins called sirtuins — Hst3p and Hst4p — causes cells to become hypersensitive to chemical agents and temperature and to spontaneously break and/or lose chromosomes. In humans, the loss or breakage of chromosomes can cause cells to lose control of when and if they are supposed to divide, becoming cancerous.

Nearly every human cell contains about six feet of DNA packaged into chromosomes. Chromosomes consist of DNA wrapped around a scaffold-like structure made of proteins called histones. Each time a cell divides into two, all of this DNA must be copied exactly and repackaged properly with histones to form chromosomes in the new cell.

During the copying process, new chromosomes often have breaks in them that need to be sealed before the chromosome is considered “finished” and the cell is ready to divide into two. All cells have damage control mechanisms that can sense nicks and breaks in chromosomes — DNA damage — and repair them.

“We think acetylation somehow marks the newly copied DNA so the cell knows to repair the breaks,” says Boeke. “Once the breaks are repaired, the acetyl groups no longer are needed and are removed in normal cells.”

Sirtuins Hst3p and Hst4p are proteins required to remove these specific chemical “decorations” — ca
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