DNA polymerase η contributes to strand bias of mutations of A versus T in immunoglobulin genes

Vladimir I. Mayorov, Igor B. Rogozin, Linda R. Adkison, Patricia J. Gearhart

Research output: Contribution to journalArticle

Abstract

DNA polymerase (pol) η 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 η 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 η. 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 η generates more mutations of A than T on the nontranscribed strand. This in vivo data from polymerase η-deficient B cells correlates well with the in vitro specificity of the enzyme. Because polymerase η inserts more mutations opposite template T than template A, it would generate more substitutions of A on the newly synthesized strand.

Original languageEnglish (US)
Pages (from-to)7781-7786
Number of pages6
JournalJournal of Immunology
Volume174
Issue number12
Publication statusPublished - Jun 15 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Mayorov, V. I., Rogozin, I. B., Adkison, L. R., & Gearhart, P. J. (2005). DNA polymerase η contributes to strand bias of mutations of A versus T in immunoglobulin genes. Journal of Immunology, 174(12), 7781-7786.