|NIEHS Researchers Identify Enzyme Critical in
In this week’s issue of Science, researchers from the
National Institute of Environmental Health Sciences (NIEHS) and
Umeö University in Sweden report an important discovery about a
critical new role that an enzyme called DNA polymerase epsilon
plays in replicating DNA in higher organisms such as yeast and
perhaps even humans.
“The study places us one step closer to understanding the origins
of genome instability that underlie certain environmental diseases
in humans,” said NIEHS Director David A. Schwartz, M.D. NIEHS is
part of the National Institutes of Health.
The research was conducted by Zachary Pursell, Ph.D. and Thomas
A. Kunkel, Ph.D., at NIEHS in collaboration with Erik Johansson,
Ph.D. and colleagues at Umeå University.
The researchers used an innovative strategy to demonstrate that
in bakers yeast, DNA polymerase epsilon has a primary role in replicating
the leading strand of DNA. DNA polymerase epsilon was found to
be a key determinant of genome stability and of cellular responses
to DNA damage resulting from exposures to environmental stress.
The researchers built on fundamental discoveries on the structure
and replication of DNA made by Nobel laureates James Watson, Francis
Crick and Arthur Kornberg.
When Watson and Crick first described the structure of DNA in
1953, they pointed out that the two DNA strands, which are referred
to as leading and lagging, pair with each other to form the now
familiar double helix.
Shortly thereafter, Kornberg and colleagues discovered the first
enzymes capable of replicating DNA, a process required to make
new genomes for cell division. These enzymes, called DNA polymerases,
were shown to copy the two DNA strands in only one of two possible
directions. One strand of the double helix must be replicated first
by a dedicated leading strand polymerase, followed slightly thereafter
by replication of the lagging strand by a different polymerase.
In lower organisms like the E. coli bacteria that Kornberg
studied, one DNA polymerase can accomplish both tasks. However,
humans and related higher organisms, such as bakers yeast, are
much more complicated. Recent discoveries, several of which emerged
from the human genome project, indicate that the human genome encodes
at least 15 DNA polymerases that can copy DNA. Several of these
are thought to perform genomic replication, while others operate
under special circumstances, such as the repair of DNA damage resulting
from environmental exposures.
“Amazingly, more than a half century after Watson and Crick first
described the DNA double helix, it had remained unclear which of
these many DNA polymerases in higher organisms is actually responsible
for first replicating the leading strand during nuclear genome
duplication, “ said Kunkel, author and Chief, Laboratory of Structural
Biology at NIEHS.
Kunkel explained that the general strategy used in the study can
now be applied to investigate other reactions that are critical
for genome stability, including the identity of the lagging strand
polymerase and the roles of more specialized DNA polymerases in
copying damaged DNA.
According to Pursell, a researcher in the DNA Replication Fidelity
Group at NIEHS and first author on the paper the study’s findings
advance the fundamental understanding of how the genomes of many
higher organisms are replicated.
The National Institute of Environmental Health Sciences (NIEHS),
a component of the National Institutes of Health, supports research
to understand the effects of the environment on human health. For
more information on environmental health topics, please visit our
website at http://www.niehs.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Pursell ZF, Isoz I, Lundström EB, Johannsson
E, Kunkel TA. Yeast DNA Polymerase e Participates in Leading-Strand
DNA Replication. Science, 2007.