Sci. Aging Knowl. Environ., 25 May 2005
Hush, Little Gene
Mystery molecule helps gene-quieting protein mothball DNA
As new mothers quickly learn, quieting a howling infant is easier if you've got support. To quiet genes, the protein Sir2p makes its own helper, new research on yeast reveals. The molecular assistant coaxes proteins to gather into a gene-blocking formation. The work raises the possibility that the same mechanism operates in mammals.
Sir2 proteins have garnered a lot of attention because they prolong life in organisms such as worms and yeast (see Kaeberlein Perspective). The molecule helps close down, or silence, stretches of genes by pairing with the protein Sir4p and fastening onto DNA. Then another protein, Sir3p, hooks on, and the molecular trio forms a DNA-silencing conglomeration. Once one of these Sir teams attaches, others adhere farther down the chromosome and shut off their DNA neighborhoods. However, researchers don't know what catalyzes these additional dockings. And other mysteries surround Sir2p's actions. The molecule chops acetyl groups off the histone proteins around which DNA coils, and this amputation spurs silencing. But removing acetyls spawns an enigmatic molecule known as AAR, which might also help gag genes. Moreover, Sir3p molecules can link up into chains, and boosting production of the protein causes more DNA to shut down. Molecular biologist Danesh Moazed of Harvard Medical School in Boston and colleagues wanted to determine whether AAR and the Sir3 chains play a role in silencing.
First, they probed the composition of Sir triplets. If Sir2p can't remove acetyl groups from histones, some Sir3p binds to the Sir2p/Sir4p duos. When Sir2p deposes acetyl groups, however, more Sir3p joins the silencing conglomerations, the researchers found. The scientists observed with the electron microscope that the removal of acetyl groups spurred the Sir amalgam to transform from a blob into a cylinder. Adding AAR to their test-tube system also triggered this change in shape and boosted the amount of Sir3p clinging to the Sir composites. That observation hints that Sir3p addition promotes the reconfiguration and indicates that AAR helps to resculpt the Sir-containing aggregations, says Moazed, and it might also explain how silencing spreads. Because AAR recruits Sir3p to the silencing complexes, it might spur the formation of Sir3p chains and expand the silenced region along the chromosome. The conglomeration's shape change might signify that these chains have formed.
'It's an important finding," says molecular biologist Leonard Guarente of the Massachusetts Institute of Technology. "It's the first paper I'm aware of that shows a role for AAR in silencing," he says, and it raises the possibility that AAR also helps shut down genes in mammals. The work also solves the puzzle of why cells adopt what seems to be "an unnecessarily baroque mechanism" to remove acetyl groups, says structural biologist Cynthia Wolberger of Johns Hopkins University School of Medicine in Baltimore, Maryland. Lopping off acetyl groups destroys NAD, a compound that costs the cell plenty to fashion. But the study suggests that AAR is important, indicating that the energy expenditure makes sense for the cell, she says: "I've always believed that nature wouldn't do something so incredibly wasteful." Further work might reveal more about how Sir2p recruits good help.
May 25, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150