VRrm Rrm: Rrm protein jump-starts idle DNA-copying equipment (Genome instability; DNA replication)
Authors: Beckman Mary 
Published: August 2003

When a job becomes boring, a worker sometimes needs a kick in the pants. Inside yeast cells, proteins that copy DNA slack off occasionally, especially when the sequences get repetitive. New research identifies a protein that rouses these enzymes when they stall on monotonous stretches, such as those at the ends of chromosomes. By nudging the copying machinery through tedious DNA sections, the protein ensures chromosomal integrity. Because unstable genomes promote cancer and possibly aging, this protein might occupy a novel cranny in the cupboard of long life.

Repetitive DNA sequences--in which the same short bit is slapped down over and over again--called telomeres protect genes from frittering away when the ends of chromosomes shrink as cells copy their DNA. Chromosomes that lose too much telomeric DNA can stick together and tear during cell division. The resulting genetic chaos leads to genomic instability, which triggers senescence, uncontrolled growth, or cell death (see
"Dangerous Liaisons"
). Furthermore, these types of chromosomal rearrangements typify the premature aging condition Werner syndrome (see
"Of Hyperaging and Methuselah Genes"
and
Fry Review
).

Other recurring sequences seem to spur yeast aging. Previously, scientists found a DNA-unraveling protein, Rrm3p, that accelerates replication of ribosomal DNA (rDNA) and limits the production of rDNA circles, molecular loops known to reduce the number of times a yeast cell can reproduce (see
Kaeberlein Perspective
). Because telomeres and rDNA are highly repetitive, Ivessa and colleagues investigated whether Rrm3p promotes telomere maintenance, just as it helps keep rDNA intact.

To probe Rrm3p's role at chromosome ends, the researchers tested whether the protein influences the speed of DNA replication. They isolated forked DNA molecules that arise as cells duplicate chromosomes and separated them according to size. The bigger the forked DNA, the farther the copying enzymes have advanced along the chromosome. In cells without Rrm3p, the replication machinery moved through the telomeric DNA at about 1/10 the speed as when the protein was present, indicating that Rrm3p hurries the copying equipment along. Rrm3p probably protects the chromosome from the many consequences of stalled replication machinery, such as double-stranded breaks, says Virginia Zakian, a molecular biologist at Princeton University who led the team. Despite Rrm3p's significance for DNA replication, cells that lack it don't suffer chromosome loss or scrambling, hinting at the existence of a robust backup system.
If Rrm3p's pushiness does guard telomeres, it could preserve the yeast genome in ways other than by preventing DNA breaks. Molecular biologist Bradley Johnson of the University of Pennsylvania Medical School in Philadelphia speculates that Rrm3p's ability to help keep chromosomes clear of stalled replication machinery could discourage DNA from hooking up in inappropriate ways. The protein's capacity to curb rDNA circle formation suggests that it combats yeast decrepitude; its potential role in maintaining genome stability raises the possibility that a similar protein might operate in human aging as well. If so, then picking up the pace of DNA copying might hustle creatures to longer life.
--Mary Beckman

A. S. Ivessa, J.-Q. Zhou, V. P. Schulz, E. K. Monson, V. A. Zakian,
Saccharomyces
Rrm3p, a 5′ to 3′ DNA helicase that promotes replication fork progression through telomeric and subtelomeric DNA.
Genes Dev.
16
, 1383-1396 (2002).
[Abstract]
[Full Text]