title: Different mutation signatures in DNA polymerase eta- and MSH6-deficient mice suggest separate roles in antibody diversification.
abstract: Hypermutation in immunoglobulin genes produces a high frequency of substitutions of all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for DNA polymerase (pol) eta have decreased substitutions of A.T base pairs in variable and switch regions. To study the role of pol eta in a genetically tractable system, we created mice lacking pol eta. B cells from Polh-/- mice produced normal amounts of IgG, indicating that pol eta does not affect class switch recombination. Similar to their human counterparts, variable and switch regions from Polh-/- mice had fewer substitutions of A.T base pairs and correspondingly more mutations of C.G base pairs, which firmly establishes a central role for pol eta in hypermutation. Notably, the location and types of substitutions differ markedly from those in Msh6-/- clones, which also have fewer A.T mutations. The data suggest that pol eta preferentially synthesizes a repair patch on the nontranscribed strand, whereas MSH6 functions to generate the patch.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Stella A
authors.initials: SA
authors.lastname: Martomo
authors.forename: William W
authors.initials: WW
authors.lastname: Yang
authors.forename: Robert P
authors.initials: RP
authors.lastname: Wersto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ohkumo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kondo
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokoi
authors.forename: Chikahide
authors.initials: C
authors.lastname: Masutani
authors.forename: Fumio
authors.initials: F
authors.lastname: Hanaoka
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005434:Flow Cytometry; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D000099270:Y-Family DNA Polymerases
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D007074:Immunoglobulin G; C102997:Msh6 protein, mouse; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases