Somatic hypermutation of immunoglobulin genes: lessons from proliferating cell nuclear antigenK164R mutant mice

Proliferating cell nuclear antigen (PCNA) encircles DNA as a ring-shaped homotrimer and, by tethering DNA polymerases to their template, PCNA serves as a critical replication factor. In contrast to high-fidelity DNA polymerases, the activation of low-fidelity translesion synthesis (TLS) DNA polymera...

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Vydáno v:Philosophical transactions of the Royal Society of London. Series B. Biological sciences Ročník 364; číslo 1517; s. 621
Hlavní autoři: Langerak, Petra, Krijger, Peter H L, Heideman, Marinus R, van den Berk, Paul C M, Jacobs, Heinz
Médium: Journal Article
Jazyk:angličtina
Vydáno: England 12.03.2009
Témata:
Animals
DNA Mutational Analysis
DNA Repair
DNA-Directed DNA Polymerase - metabolism
Mice
Mice, Mutant Strains
Models, Genetic
Nucleotidyltransferases - metabolism
Proliferating Cell Nuclear Antigen - genetics
Proliferating Cell Nuclear Antigen - metabolism
Somatic Hypermutation, Immunoglobulin - genetics
Ubiquitination
ISSN:1471-2970, 1471-2970
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Shrnutí:Proliferating cell nuclear antigen (PCNA) encircles DNA as a ring-shaped homotrimer and, by tethering DNA polymerases to their template, PCNA serves as a critical replication factor. In contrast to high-fidelity DNA polymerases, the activation of low-fidelity translesion synthesis (TLS) DNA polymerases seems to require damage-inducible monoubiquitylation (Ub) of PCNA at lysine residue 164 (PCNA-Ub). TLS polymerases can tolerate DNA damage, i.e. they can replicate across DNA lesions. The lack of proofreading activity, however, renders TLS highly mutagenic. The advantage is that B cells use mutagenic TLS to introduce somatic mutations in immunoglobulin (Ig) genes to generate high-affinity antibodies. Given the critical role of PCNA-Ub in activating TLS and the role of TLS in establishing somatic mutations in immunoglobulin genes, we analysed the mutation spectrum of somatically mutated immunoglobulin genes in B cells from PCNAK164R knock-in mice. A 10-fold reduction in A/T mutations is associated with a compensatory increase in G/C mutations-a phenotype similar to Poleta and mismatch repair-deficient B cells. Mismatch recognition, PCNA-Ub and Poleta probably act within one pathway to establish the majority of mutations at template A/T. Equally relevant, the G/C mutator(s) seems largely independent of PCNAK(164) modification.
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ISSN:1471-2970
1471-2970
DOI:10.1098/rstb.2008.0223