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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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