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The Journal of Immunology, 2005, 174: 7781-7786.
Copyright © 2005 by The American Association of Immunologists

DNA Polymerase {eta} Contributes to Strand Bias of Mutations of A versus T in Immunoglobulin Genes1

Vladimir I. Mayorov*, Igor B. Rogozin{dagger},{ddagger}, Linda R. Adkison* and Patricia J. Gearhart2,§

* Department of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA 31207; {dagger} National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894; {ddagger} Institute of Cytology and Genetics, Novosibirsk, Russia; and § Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

DNA polymerase (pol) {eta} participates in hypermutation of A:T bases in Ig genes because humans deficient for the polymerase have fewer substitutions of these bases. To determine whether polymerase {eta} is also responsible for the well-known preference for mutations of A vs T on the nontranscribed strand, we sequenced variable regions from three patients with xeroderma pigmentosum variant (XP-V) disease, who lack polymerase {eta}. The frequency of mutations in the intronic region downstream of rearranged JH4 gene segments was similar between XP-V and control clones; however, there were fewer mutations of A:T bases and correspondingly more substitutions of C:G bases in the XP-V clones (p < 10–7). There was significantly less of a bias for mutations of A compared with T nucleotides in the XP-V clones compared with control clones, whereas the frequencies for mutations of C and G were identical in both groups. An analysis of mutations in the WA sequence motif suggests that polymerase {eta} generates more mutations of A than T on the nontranscribed strand. This in vivo data from polymerase {eta}-deficient B cells correlates well with the in vitro specificity of the enzyme. Because polymerase {eta} inserts more mutations opposite template T than template A, it would generate more substitutions of A on the newly synthesized strand.




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