The Journal of Experimental Medicine
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Published online 29 March 2004 doi:10.1084/jem.20032022
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 917-924
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Absence of DNA Polymerase {eta} Reveals Targeting of C Mutations on the Nontranscribed Strand in Immunoglobulin Switch Regions

Xianmin Zeng, George A. Negrete, Cynthia Kasmer, William W. Yang, and Patricia J. Gearhart

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

Address correspondence to Patricia J. Gearhart, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224. Phone: (410) 558-8561; Fax: (410) 558-8157; email: gearhartp{at}grc.nia.nih.gov

Activation-induced cytosine deaminase preferentially deaminates C in DNA on the nontranscribed strand in vitro, which theoretically should produce a large increase in mutations of C during hypermutation of immunoglobulin genes. However, a bias for C mutations has not been observed among the mutations in variable genes. Therefore, we examined mutations in the µ and {gamma} switch regions, which can form stable secondary structures, to look for C mutations. To further simplify the pattern, mutations were studied in the absence of DNA polymerase (pol) {eta}, which may produce substitutions of nucleotides downstream of C. DNA from lymphocytes of patients with xeroderma pigmentosum variant (XP-V) disease, whose polymerase {eta} is defective, had the same frequency of switching to all four {gamma} isotypes and hypermutation in µ-{gamma} switch sites (0.5% mutations per basepair) as control subjects. There were fewer mutations of A and T bases in the XP-V clones, similar to variable gene mutations from these patients, which confirms that polymerase {eta} produces substitutions opposite A and T. Most importantly, the absence of polymerase {eta} revealed an increase in C mutations on the nontranscribed strand. This data shows for the first time that C is preferentially mutated in vivo and pol {eta} generates hypermutation in the µ and {gamma} switch regions.

Key Words: somatic hypermutation • activation-induced cytosine deaminase • xeroderma pigmentosum variant • gap-filling repair • translesion replication

The online version of this article contains supplemental material.

Abbreviations used in this paper: AID, activation-induced cytosine deaminase; pol, DNA polymerase; XP-V, xeroderma pigmentosum variant.


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