DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination.
Base substitutions, deletions, and duplications are observed at the immunoglobulin locus in DNA sequences involved in class switch recombination (CSR). These mutations are dependent upon activation-induced cytidine deaminase (AID) and present all the characteristics of the ones observed during V gene somatic hypermutation, implying that they could be generated by the same mutational complex. It has been proposed, based on the V gene mutation pattern of patients with the cancer-prone xeroderma pigmentosum variant (XP-V) syndrome who are deficient in DNA polymerase eta (pol eta), that this enzyme could be responsible for a large part of the mutations occurring on A/T bases. Here we show, by analyzing switched memory B cells from two XP-V patients, that pol eta is also an A/T mutator during CSR, in both the switch region of tandem repeats as well as upstream of it, thus suggesting that the same error-prone translesional polymerases are involved, together with AID, in both processes.
Faili
Ahmad
A
INSERM U373, Faculté de Médecine Necker-Enfants Malades, Université Paris V, France.
Aoufouchi
Said
S
Weller
Sandra
S
Vuillier
Françoise
F
Stary
Anne
A
Sarasin
Alain
A
Reynaud
Claude-Agnès
CA
Weill
Jean-Claude
JC
D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D007438:Introns; D008875:Middle Aged; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D014983:Xeroderma Pigmentosum / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099270:Y-Family DNA Polymerases
D003564:Cytidine Deaminase; D043525:Cytosine Deaminase; D004247:DNA; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases