Limits...
DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination.

Faili A, Aoufouchi S, Weller S, Vuillier F, Stary A, Sarasin A, Reynaud CA, Weill JC - J. Exp. Med. (2004)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U373, Faculté de Médecine Necker-Enfants Malades, Université Paris V, France.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Mutation pattern of Sμ–Sα junctions in normal controls and XP-V patients. (a) Mutation distribution along the first 250 bp of the Sμ region in Sμ–Sα junctions. Mutations collected from normal controls are listed above the reference sequence, and mutations from XP-V patients are below. The G position of the RGYW motif (and the C position of the complementary WRCY motif on the other strand) is highlighted in gray. (b) Nucleotide substitution preference of mutations in Sμ–Sα junctions. Mutations collected on both Sμ and Sα regions are tabulated, first as raw proportions and then after correction for base composition, taking into account the base composition of the average region sequenced in each case. Sμ controls: 170 bp, 25.9% A, 30.0% G, 22.3% C, and 21.8% T; Sα controls: 211 bp, 12.6% A, 47.6% G, 18.6% C, and 21.2% T; Sμ-XP-V: 200 bp, 25.5% A, 31% G, 22% C, and 21.5% T; Sα-XP-V: 350 bp, 12.9% A, 46.1% G, 19.6% C, and 21.4% T.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211761&req=5

fig3: Mutation pattern of Sμ–Sα junctions in normal controls and XP-V patients. (a) Mutation distribution along the first 250 bp of the Sμ region in Sμ–Sα junctions. Mutations collected from normal controls are listed above the reference sequence, and mutations from XP-V patients are below. The G position of the RGYW motif (and the C position of the complementary WRCY motif on the other strand) is highlighted in gray. (b) Nucleotide substitution preference of mutations in Sμ–Sα junctions. Mutations collected on both Sμ and Sα regions are tabulated, first as raw proportions and then after correction for base composition, taking into account the base composition of the average region sequenced in each case. Sμ controls: 170 bp, 25.9% A, 30.0% G, 22.3% C, and 21.8% T; Sα controls: 211 bp, 12.6% A, 47.6% G, 18.6% C, and 21.2% T; Sμ-XP-V: 200 bp, 25.5% A, 31% G, 22% C, and 21.5% T; Sα-XP-V: 350 bp, 12.9% A, 46.1% G, 19.6% C, and 21.4% T.

Mentions: Sequences listed in Fig. 3 are tabulated.


DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination.

Faili A, Aoufouchi S, Weller S, Vuillier F, Stary A, Sarasin A, Reynaud CA, Weill JC - J. Exp. Med. (2004)

Mutation pattern of Sμ–Sα junctions in normal controls and XP-V patients. (a) Mutation distribution along the first 250 bp of the Sμ region in Sμ–Sα junctions. Mutations collected from normal controls are listed above the reference sequence, and mutations from XP-V patients are below. The G position of the RGYW motif (and the C position of the complementary WRCY motif on the other strand) is highlighted in gray. (b) Nucleotide substitution preference of mutations in Sμ–Sα junctions. Mutations collected on both Sμ and Sα regions are tabulated, first as raw proportions and then after correction for base composition, taking into account the base composition of the average region sequenced in each case. Sμ controls: 170 bp, 25.9% A, 30.0% G, 22.3% C, and 21.8% T; Sα controls: 211 bp, 12.6% A, 47.6% G, 18.6% C, and 21.2% T; Sμ-XP-V: 200 bp, 25.5% A, 31% G, 22% C, and 21.5% T; Sα-XP-V: 350 bp, 12.9% A, 46.1% G, 19.6% C, and 21.4% T.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211761&req=5

fig3: Mutation pattern of Sμ–Sα junctions in normal controls and XP-V patients. (a) Mutation distribution along the first 250 bp of the Sμ region in Sμ–Sα junctions. Mutations collected from normal controls are listed above the reference sequence, and mutations from XP-V patients are below. The G position of the RGYW motif (and the C position of the complementary WRCY motif on the other strand) is highlighted in gray. (b) Nucleotide substitution preference of mutations in Sμ–Sα junctions. Mutations collected on both Sμ and Sα regions are tabulated, first as raw proportions and then after correction for base composition, taking into account the base composition of the average region sequenced in each case. Sμ controls: 170 bp, 25.9% A, 30.0% G, 22.3% C, and 21.8% T; Sα controls: 211 bp, 12.6% A, 47.6% G, 18.6% C, and 21.2% T; Sμ-XP-V: 200 bp, 25.5% A, 31% G, 22% C, and 21.5% T; Sα-XP-V: 350 bp, 12.9% A, 46.1% G, 19.6% C, and 21.4% T.
Mentions: Sequences listed in Fig. 3 are tabulated.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U373, Faculté de Médecine Necker-Enfants Malades, Université Paris V, France.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus