UNG shapes the specificity of AID-induced somatic hypermutation

Pérez-Durán, Pablo; Belver, Laura; Yébenes, Virginia G. de; Delgado, Pilar; Pisano, David G.; Ramiro, Almudena R.

doi:10.1084/jem.20112253

Cited by 44 publications

(53 citation statements)

References 60 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A strong bias of mutations at C:G base pairs suggests a preferential recognition of the UNG pathway (17). Previous studies showed that sequence context influences UNG-initiated error-prone versus error-free repair of AID-induced lesions (44). Thus, we propose that the initial U:G lesion in S regions is located in a sequence context facilitating its recognition by UNG, which in turn leads to more DSBs.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Target Sequences and Repair Pathways Determines Distinct Outcomes of AID-Initiated Lesions

Chen

Eder

Elos

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Activation-induced deaminase (AID) functions by deaminating cytosines and causing U:G mismatches, a rate-limiting step of antibody gene diversification. However, precise mechanisms regulating AID-deamination frequency remain incompletely understood. Moreover, it is unknown whether different sequence contexts influence the preferential access of mismatch repair (MMR) or uracil glycosylase (UNG) to AID-initiated U:G mismatches. Here, we employed two knock-in models to directly compare the mutability of core Sµ and VDJ exon sequences and their ability to regulate AID-deamination and subsequent repair process. We find that S region is a much more efficient AID deamination target than V region. Igh locus AID-initiated lesions are processed by error-free and error-prone repair. S region U:G mismatches are preferentially accessed by UNG, leading to more UNG-dependent deletions, enhanced by MMR deficiency. V region mutation hotspots are largely determined by AID deamination. Recurrent and conserved S region motifs potentially function as spacers between AID-deamination hotspots. We conclude that the pattern of mutation hotspots and DNA break generation is influenced by sequence-intrinsic properties, which regulate AID deamination and affect the preferential access of downstream repair. Our studies reveal an evolutionarily conserved role for substrate sequences in regulating antibody gene diversity and AID targeting specificity.

show abstract

Section: Discussionmentioning

confidence: 99%

Interplay between Target Sequences and Repair Pathways Determines Distinct Outcomes of AID-Initiated Lesions

Chen

Eder

Elos

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…If uracil is removed by UNG2, the abasic site is subject to translesion synthesis, principally by Pol h (eta), giving rise to a wider spectrum of mutations. The properties of UNG2 are uniquely suited for the purpose and cannot be substituted by SMUG1 under physiological conditions Perez-Duran et al 2012). The role of UNG2, AID, mismatch repair proteins, and NHEJ proteins in adaptive immunity has been extensively reviewed and shall not be further elaborated here (Di Noia and Neuberger 2007;Maul and Gearhart 2010a,b;Stavnezer 2011).…”

Section: Adaptive Immunity By Mutagenic Processing Of U:g Mismatches-mentioning

confidence: 99%

Base Excision Repair

Krokan

Bjørås

2013

Cold Spring Harbor Perspectives in Biology

957

774

View full text Add to dashboard Cite

Base excision repair (BER) corrects DNA damage from oxidation, deamination and alkylation. Such base lesions cause little distortion to the DNA helix structure. BER is initiated by a DNA glycosylase that recognizes and removes the damaged base, leaving an abasic site that is further processed by short-patch repair or long-patch repair that largely uses different proteins to complete BER. At least 11 distinct mammalian DNA glycosylases are known, each recognizing a few related lesions, frequently with some overlap in specificities. Impressively, the damaged bases are rapidly identified in a vast excess of normal bases, without a supply of energy. BER protects against cancer, aging, and neurodegeneration and takes place both in nuclei and mitochondria. More recently, an important role of uracil-DNA glycosylase UNG2 in adaptive immunity was revealed. Furthermore, other DNA glycosylases may have important roles in epigenetics, thus expanding the repertoire of BER proteins.

show abstract

“…DNA was extracted, and the Sm and J H 4 regions were PCR-amplified using specific oligonucleotides (supplemental Methods). Amplification products were purified and sequenced by next-generation sequencing (NGS) 28 or cloned and sequenced by conventional Sanger sequencing.…”

Section: Somatic Mutation Analysismentioning

confidence: 99%

“…28 No mutations were detected in B cells isolated from AID 2/2 mice, used as a negative control. We detected total Figure 3B), confirming that miR-217 overexpression in B cells increases the load of SHM in GCs.…”

Section: Mir-217 Expression Enhances the Gc Reactionmentioning

confidence: 99%