MIT's Angelika Amon and her colleagues report in Science this week that aneuploidy leads to genomic instability in yeast. The researchers studied 13 haploid Saccharomyces cerevisiae strains that had extra copies of a single chromosome, and whether those strains had segregation fidelity. Compared to a control, those strains had an increased rate of mis-segregation. Amon et al. then found that aneuploid strains had a higher mutation rate as well as an increased number of double-stranded breaks during replication. "This study establishes that missegregation of a single chromosome is sufficient to induce the hallmarks of genomic instability, including whole-chromosome instability, mutagenesis, and sensitivity to genotoxic stress," Amon and her colleagues write.
Also in Science, Georgetown University School of Medicine's Todd Waldman and his team found that inactivation of STAG2, a gene that encodes a cohesin complex subunit, causes aneuploidy in human cancer. Targeted inactivation of STAG2 in a human cell line with a stable karyotype led to chromatid cohesion defects and aneuploidy, the researchers report, while targeted correction of mutant STAG2 alleles led to chromosomal stability in glioblastoma cell lines. "We postulate that STAG2 is likely to function as a 'caretaker' tumor suppressor gene that when inactivated results in chromosomal instability, similar to other caretaker genes," Waldman's team writes.
A commentary on both the above papers notes that chromosomal abnormalities like aneuploidy are hallmarks of cancer and that these studies "show that aneuploidy enhances genetic recombination and defective DNA damage repair, thereby providing a mechanistic link between aneuploidy and genomic instability."
In Science Translational Medicine, Atul Butte at Stanford University and his colleagues report a new computational approach to repositioning drugs. "We integrated gene expression measurements from 100 diseases and gene expression measurements on 164 drug compounds, yielding predicted therapeutic potentials for these drugs," Butte et al. say. The researchers add they found many established drug-diseases relationships, and they experimentally validated a prediction that the antiulcer drug cimetidine could treat lung adenocarcinoma.