Tandem Substitutions in Somatic Hypermutation

Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem substitutions may also occur. We investigated...

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Veröffentlicht in:Frontiers in immunology Jg. 12; S. 807015
Hauptverfasser: Sepúlveda-Yáñez, Julieta H., Alvarez Saravia, Diego, Pilzecker, Bas, van Schouwenburg, Pauline A., van den Burg, Mirjam, Veelken, Hendrik, Navarrete, Marcelo A., Jacobs, Heinz, Koning, Marvyn T.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers Media S.A 07.01.2022
Schlagworte:
Alleles
apyrimidinic site
Codon
DNA Mismatch Repair
High-Throughput Nucleotide Sequencing
Humans
Immunoglobulin Heavy Chains - genetics
Immunology
Mutation
Receptors, Antigen, B-Cell - genetics
Somatic Hypermutation, Immunoglobulin
strand slippage
tandem dinucleotide substitutions (TDNS)
Tandem Repeat Sequences
tandem substitution
translesion synthesis (TLS)
uracil-N-glycosylase (UNG)
V(D)J Recombination
tandem substitution
tandem dinucleotide substitutions (TDNS)
translesion synthesis (TLS)
uracil-N-glycosylase (UNG)
strand slippage
apyrimidinic site
ISSN:1664-3224, 1664-3224
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Zusammenfassung:Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem substitutions may also occur. We investigated incidence and sequence context of tandem substitutions by massive parallel sequencing of V(D)J repertoires in healthy human donors. Mutation patterns were congruent with SHM-derived single nucleotide mutations, delineating initiation of the tandem substitution by AID. Tandem substitutions comprised 5,7% of AID-induced mutations. The majority of tandem substitutions represents single nucleotide juxtalocations of directly adjacent sequences. These observations were confirmed in an independent cohort of healthy donors. We propose a model where tandem substitutions are predominantly generated by translesion synthesis across an apyramidinic site that is typically created by UNG. During replication, apyrimidinic sites transiently adapt an extruded configuration, causing skipping of the extruded base. Consequent strand decontraction leads to the juxtalocation, after which exonucleases repair the apyramidinic site and any directly adjacent mismatched base pairs. The mismatch repair pathway appears to account for the remainder of tandem substitutions. Tandem substitutions may enhance affinity maturation and expedite the adaptive immune response by overcoming amino acid codon degeneracies or mutating two adjacent amino acid residues simultaneously.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Present address: Marvyn T. Koning, Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
Reviewed by: Yu Zhang, Western Michigan University, United States; Richard Chahwan, University of Zurich, Switzerland
This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology
Edited by: Sylvie Hermouet, U1232 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA)(INSERM), France
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2021.807015