Mutating for Good: DNA Damage Responses During Somatic Hypermutation

Somatic hypermutation (SHM) of immunoglobulin ( ) genes plays a key role in antibody mediated immunity. SHM in B cells provides the molecular basis for affinity maturation of antibodies. In this way SHM is key in optimizing antibody dependent immune responses. SHM is initiated by targeting the Activ...

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Published in:Frontiers in immunology Vol. 10; p. 438
Main Authors: Pilzecker, Bas, Jacobs, Heinz
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media S.A 12.03.2019
Subjects:
abasic site
B-Lymphocytes - immunology
base excision repair
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
cytosine deamination
Deamination - physiology
DNA - genetics
DNA Damage - genetics
DNA damage tolerance (DDT)
DNA Repair - genetics
Humans
Immunology
non-canonical mismatch repair (ncMMR)
Somatic Hypermutation, Immunoglobulin - genetics
translesion synthesis (TLS)
VDJ Exons - genetics
base excision repair
non-canonical mismatch repair (ncMMR)
abasic site
translesion synthesis (TLS)
DNA damage tolerance (DDT)
cytosine deamination
ISSN:1664-3224, 1664-3224
Online Access:Get full text
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Summary:Somatic hypermutation (SHM) of immunoglobulin ( ) genes plays a key role in antibody mediated immunity. SHM in B cells provides the molecular basis for affinity maturation of antibodies. In this way SHM is key in optimizing antibody dependent immune responses. SHM is initiated by targeting the Activation-Induced Cytidine Deaminase (AID) to rearranged V(D)J and switch regions of genes. The mutation rate of this programmed mutagenesis is ~10 base pairs per generation, a million-fold higher than the non-AID targeted genome of B cells. AID is a processive enzyme that binds single-stranded DNA and deaminates cytosines in DNA. Cytosine deamination generates highly mutagenic deoxy-uracil (U) in the DNA of both strands of the loci. Mutagenic processing of the U by the DNA damage response generates the entire spectrum of base substitutions characterizing SHM at and around the initial U lesion. Starting from the U as a primary lesion, currently five mutagenic DNA damage response pathways have been identified in generating a well-defined SHM spectrum of C/G transitions, C/G transversions, and A/T mutations around this initial lesion. These pathways include (1) replication opposite template U generates transitions at C/G, (2) UNG2-dependent translesion synthesis (TLS) generates transversions at C/G, (3) a hybrid pathway comprising non-canonical mismatch repair (ncMMR) and UNG2-dependent TLS generates transversions at C/G, (4) ncMMR generates mutations at A/T, and (5) UNG2- and PCNA Ubiquitination (PCNA-Ub)-dependent mutations at A/T. Furthermore, specific strand-biases of SHM spectra arise as a consequence of a biased AID targeting, ncMMR, and anti-mutagenic repriming. Here, we review mammalian SHM with special focus on the mutagenic DNA damage response pathways involved in processing AID induced Us, the origin of characteristic strand biases, and relevance of the cell cycle.
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Reviewed by: Patricia Johanna Gearhart, National Institutes of Health (NIH), United States; Javier Marcelo Di Noia, Institute of Clinical Research De Montreal (IRCM), Canada
Edited by: Amy L. Kenter, University of Illinois at Chicago, United States
This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2019.00438