Boundary War
Authors: Beckman Mary 
Published: August 2003

Like land-hungry ranchers feuding over property lines, two enzymes draw a border between active and silent DNA by propping up stockades on chromosomes, according to new research. Where the boundary falls depends on which enzyme is blockading more busily.

The process of silencing--in which cells shut down gene activity and prevent reshuffling along large stretches of DNA--keeps yeast cells young and might also thwart aging in more complex organisms. Silencing is confined to particular regions of the genome, so scientists want to know how cells control the process. Last month, researchers who study yeast showed that silencing near chromosome ends, called telomeres, requires the continuous bustle of an enzyme that silences DNA and suggested that some other enzyme struggles to keep it active. Two groups of scientists have now found the off enzyme's nemesis and have clarified how the barricade between silent and active DNA arises.

In chromosomes, DNA wraps around proteins called histones, which help silence DNA--but only when they lack acetyl chemical groups at particular spots. Test tube experiments have suggested that one such acetyl group--on an amino acid called Lys16 in a specific histone--serves as a target for the yeast enzyme Sir2p, which silences genes by snipping off these modifications. Scientists knew that the enzyme Sas2p stamps histones with acetyl groups (see
"Oh, Behave!"
), and the two research teams wondered whether it could be battling Sir2p for chromosomal territory by decorating Lys16.

To test the idea, they exploited a third protein, Sir3p, which sits on Lys16 and prevents it from acquiring an acetyl group. The teams probed Sir3p's position on the chromosomes with and without Sas2p, Sir2p, and the acetyl attachment site. In normal cells, Sir3p mounded up near telomeres, Suka and colleagues found. In yeast strains lacking Sas2p, however, Sir3p spread out along chromosomes. This observation implies that Sas2p keeps Sir3p--and thus silenced DNA--confined to the extremities. A strain that lacked Lys16 behaved similarly, suggesting that Sas2p requires this acetyl attachment site to counteract Sir2p's silencing activities. Previous work established that Sir3p falls off DNA in the absence of Sir2p; when Suka and colleagues got rid of Sas2p in addition to Sir2p, Sir3p jumped back on. Kimura and colleagues tested the activity of sample genes near telomeres and found that they became five to eight times less active when Sas2p was missing. Together, the results suggest that Sas2p builds fences to keep Sir2p's ranch hand Sir3p from expanding silenced acreage.

Sir2p and Sas2p probably set up a dynamic border between active and silent DNA, says cell biologist David Sinclair of Harvard Medical School in Boston: "Remove one of the players, and the boundary is no longer distinct." In addition, previous work has shown that cells exert considerable control over the amounts of Sir2p and Sas2p present in the cell. "Getting the balance just right is crucial for saying how far the [silent DNA] extends." Further research is needed to determine whether a similar mechanism operates in humans, and if so, whether it erodes as people age. If it does, perhaps researchers can find molecular ranch hands to help with the upkeep.

--Mary Beckman; suggested by Greg Liszt

N. Suka, K. Luo, M. Grunstein, Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin.
Nat. Genet.
, 15 October 2002 [e-pub ahead of print].
[Abstract/Full Text]

A. Kimura, T. Umehara, M. Horikoshi, Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing.
Nat. Genet.
, 15 October 2002 [e-pub ahead of print].
[Abstract/Full Text]