DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes

Abstract

To determine whether DNA polymerase eta plays a role in the hypermutation of immunoglobulin variable genes, we examined the frequency and pattern of substitutions in variable VH6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymerase eta had genetic defects. The frequency of mutation was normal but the types of base changes were different: there was a decrease in mutations at A and T and a concomitant rise in mutations at G and C. We propose that more than one polymerase contributes to hypermutation and that if one is absent, others compensate. The data indicate that polymerase eta is involved in generating errors that occur predominantly at A and T and that another polymerase(s) may preferentially generate errors opposite G and C.

The Frameshift Infidelity of Human DNA Polymerase λ

“…14), a process responsible for generation of high affinity antibodies. Additional experimental results support this hypothesis (14,23,24). Similarly, non-templated additions are a signature of synthesis by TdT, implicating TdT in V(D)J recombination, essential for diversification of immunoglobulin genes (25).…”

Hijacked DNA repair proteins and unchained DNA polymerases

“…Second, U could be removed by uracil DNA glycosylase (UNG) to produce an abasic site, which when copied by low-fidelity DNA polymerases, would generate C:G transitions and transversions. Third, U could be recognized as a U:G mismatch by the MSH2-MSH6 mismatch repair (MMR) proteins, which would generate a gap that could be filled in by the low-fidelity DNA polymerase (pol) h to produce mutations of A:T base pairs (bp; Zeng et al 2001;Wilson et al 2005). The last two steps are also associated with strand breaks, which produce substrates for recombination during heavy-chain class switching.…”

“…Eight polymerases have been studied for their role in this process, using mice deficient in the polymerases. Polymerases i (McDonald et al 2003;Martomo et al 2006), k (Schenten et al 2002), l (Bertocci et al 2002), m (Bertocci et al 2002) and q (Masuda et al 2007;Martomo et al 2008) are either not involved or play a minor role; and pol h (Zeng et al 2001;Delbos et al 2005Delbos et al , 2007Martomo et al 2005) and Rev1 (Jansen et al 2006) are involved. The role of pol z is less clear (Diaz et al 2001) due to the nonviability of gene-deficient mice.…”

“…This criterion has established a role for pol h and Rev1. For pol h, we first reported that it is an A:T mutator (Zeng et al 2001), after observing that the frequency of mutations of A and T dropped fourfold in V genes from patients with xeroderma pigmentosum disease, who lack pol h. The frequency of mutations of G and C increased, so that the overall frequency of mutation was not changed compared to normal people, but the spectra were altered. This work was confirmed in mice deficient in pol h (Delbos et al 2005;Martomo et al 2005), where the frequency of A:T mutations was also diminished in non-coding regions around V genes.…”

B cells pay a price

“…Alternatively, the lesion could be repaired during base excision repair by nicking the top strand with an endonuclease. Polymerases Z (Zeng et al, 2001) and i (Faili et al, 2002) could then either fill in the gap with one nucleotide, or displace it and synthesize several bases. Since these polymerases are inaccurate, random mutations would be introduced at the sites of uracils.…”