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DNA repair mechanism that can lead to mutations
I received this from another list server and thought
it would be of interest, as it may indicate how cells
may mutate and become cancerous following DNA damage.
Specifically, a defective DNA polymerase, DnaE in this
case, may cause the mutation during repair.
I do not think this is surprising except that it
occurs in a class of enzymes that are supposed to
provide flawless repair.
------------------------------
Date: Thu, 17 Apr 2003 14:45:28 -0400
From: "NIH OLIB (NIH/OD)" <olib@OD.NIH.GOV>
Subject: SLOPPY REPAIR HELPS TB BUG RESIST DRUGS
U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH
NIH News
National Institute of Allergy and Infectious Diseases
(NIAID)
http://www.niaid.nih.gov
EMBARGOED FOR RELEASE
Thursday, April 17, 2003
12:00 p.m. ET
Contact:
Anne A. Oplinger
(301) 402-1663
aoplinger@niaid.nih.gov
SLOPPY REPAIR HELPS TB BUG RESIST DRUGS
Shoddy work by a DNA-repair enzyme allows
tuberculosis-
causing bacteria to develop antibiotic resistance,
scientists at the National Institute of Allergy and
Infectious Diseases (NIAID) have discovered. Reported
in
the current issue of the journal "Cell", the finding
by
Clifton E. Barry, III, Ph.D., and his colleagues in
South
Africa, could lead to new ways to treat TB without
risking
the development of drug resistance.
"Tuberculosis takes the lives of almost two million
people
each year, and eight million people develop active TB
annually," says NIAID Director Anthony S. Fauci, M.D.
"Especially alarming is the upsurge in cases of
multidrug-
resistant tuberculosis. A clearer understanding of how
TB
bacteria acquire drug resistance is essential if we
are to
control this disease," he adds.
Invading microbes, including the TB agent
Mycobacterium
tuberculosis (MTb), must withstand attacks by the
host's
immune system, adverse physical conditions, and,
often,
assaults by antibiotics and other drugs. Bacterial DNA
damaged in the fray can be repaired by enzymes. Some
bacterial DNA repair enzymes, though, are error-prone
and
often introduce mutations into the DNA strand. These
mutations increase the odds of generating strains
resistant
to antibiotics.
During her research stints in both Dr. Barry's lab and
the
laboratory of Valerie Mizrahi, Ph.D., at the
University of
Witwatersrand in South Africa, co-author Helena
Boshoff,
Ph.D., worked to uncover details of MTb's DNA repair
process. She used ultraviolet light to mimic the DNA
damage
suffered by MTb as it invades its host, and then she
examined how MTb responded. Dr. Boshoff determined
that MTb
uses a DNA polymerase, DnaE2, to repair its DNA.
"We were surprised to find that MTb uses an enzyme
from the
major DNA polymerase replication family. In other
organisms, including humans, such DNA polymerases are
responsible for making perfect copies of DNA before
the
cell divides. Other DNA polymerases in this family are
like
straight-A students; they perform almost flawlessly.
This
is the first error-prone DNA polymerase from this
family to
be identified," says Dr. Barry.
MTb has two copies of the gene encoding DnaE enzyme.
Previously, it was a mystery why the bacterium needed
multiple copies of its DNA replication enzyme gene.
With
the realization that MTb relies on DnaE2 enzyme to
introduce mutations into its DNA, thereby increasing
the
chance that drug resistance will result, this riddle
is
solved.
To learn what role the newly identified enzyme plays
in
animals, the researchers infected mice with either
normal
MTb or MTb lacking the DnaE2 gene. Mice infected with
the
normal MTb died quickly, while mice infected with the
mutant germ contained the infection more successfully,
indicating a role for DnaE2 in helping MTb persist in
the
host's cells. Finally, the researchers used mice to
evaluate DnaE2's role in the evolution of drug
resistance.
Confirming findings from the test-tube experiments,
mice
infected with wild-type MTb developed resistance to a
common antibiotic, while mice infected with strains
lacking
the gene -- and hence, the error-prone repair enzyme
-- did
not develop antibiotic resistance.
This new insight into the emergence of MTb drug
resistance
suggests ways to intervene with drugs targeted
specifically
at MTb's vital DNA repair enzyme. "For example," notes
Dr.
Barry, "therapies targeted at DnaE2 could block the
development of drug resistance in people infected with
drug-susceptible bacteria. Such a drug might also more
efficiently clear non-replicating MTb."
News releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at
<http://www.niaid.nih.gov>. (Reporters may request a
copy
of this paper by contacting the journal at (617)
397-2825
or press@cell.com).
NIAID is a component of the National Institutes of
Health
(NIH), which is an agency of the Department of Health
and
Human Services. NIAID supports basic and applied
research
to prevent, diagnose, and treat infectious and immune-
mediated illnesses, including HIV/AIDS and other
sexually
transmitted diseases, illness from potential agents of
bioterrorism, tuberculosis, malaria, autoimmune
disorders,
asthma and allergies.
REFERENCE: H I M Boshoff et al. DnaE2-mediated
inducible
mutagenesis plays a role in in vivo persistence and
the
emergence of drug resistance in Mycobacterium
tuberculosis.
"Cell" 113(2): 183-93 (2003).
--------------------
=====
-- John
John Jacobus, MS
Certified Health Physicist
e-mail: crispy_bird@yahoo.com
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