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Sloppy Polymerases Make Good

 
  May, 28 2001 23:49
your information resource in human molecular genetics
 
     
Nature Immunology pages 530-536 and 537-541
News and Views pages 484-485

Our bodies contain specialized immune cells, B cells, that synthesize antibodies to viruses, bacteria and their toxic products, such as tetanus toxin. When we encounter the same pathogens a second or a third time, B cells produce antibodies that are better at recognizing their "prey". Antigen-activated B cells accomplish this task by selectively mutating the antibody-encoding genes in a process known as somatic hypermutation, but how they perform this mutagenesis has largely remained unknown. Now, study of a genetic disease, together with an independently performed basic research study, has revealed some basic insights into this process. The two papers appear in the June issue of Nature Immunology (Vol. 2, No. 6) and identify one of the culprits responsible for generating these mutations.

Gearhart and colleagues in Baltimore, MD, examined antibody-encoding genes from patients with xeroderma pigmentosum type V (XP-V) disease, a condition that leads to a higher risk for sunlight-induced skin cancers. The XPV gene, mutated in XP-V patients, encodes a DNA polymerase, DNA pol h (eta), an enzyme that can replicate DNA but is much sloppier at this than the DNA polymerase that normally handles the job of DNA replication (something that must be done every time a cell divides). Thus it introduces many errors in the DNA sequence as it proceeds. It turns out that, compared to the mutations found in people without a mutated DNA pos h, patients with XP-V have dramatically altered patterns of mutations. Kunkel’s group in North Carolina examined the “mistake-patterns” that various DNA polymerases make and found that pol h frequently misincorporates nucleotides at specific A residues opposite template Ts, part of the same pattern seen in the patients.

Ursula Storb, from the University of Chicago, discusses these two papers in an accompanying News & Views.

Patricia J. Gearhart
National Institutes of Health
NIA, Laboratory of Molecular Genetics
5600 Nathan Shock Drive
Baltimore, MD 21224-6823
UNITED STATES
Tel: (+1) 410-558-8561
Fax: (+1) 410-558-8157
gearhartp@grc.nia.nih.gov

Thomas A. Kunkel
National Institutes of Health
NIEHS, Building 101, Room E342B
Laboratory of Molecular Genetics, E3-01
111 T. W. Alexander Drive
Research Triangle Park, NC 27709
UNITED STATES
Tel: (+1) 919-541-2644
Fax: (+1) 919-541-7613
kunkel@niehs.nih.gov

Ursula Storb
University of Chicago
Department of Molecular Genetics
and Cell Biology
920 E 58th St
Chicago, IL 60637-1432
UNITED STATES
Tel: (+1) 773-702-4440
Fax: (+1) 773-702-3172
stor@midway.uchicago.edu

(C) Nature Immunology press release.


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