Article

A critical role for REV1 in regulating the induction of C:G transitions and A:T mutations during Ig gene hypermutation.

Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan.
The Journal of Immunology (impact factor: 5.79). 09/2009; 183(3):1846-50. DOI:10.4049/jimmunol.0901240 pp.1846-50
Source: PubMed

ABSTRACT REV1 is a deoxycytidyl transferase that catalyzes the incorporation of deoxycytidines opposite deoxyguanines and abasic sites. To explore the role of its catalytic activity in Ig gene hypermutation in mammalian cells, we have generated mice expressing a catalytically inactive REV1 (REV1AA). REV1AA mice developed normally and were fertile on a pure C57BL/6 genetic background. B and T cell development and maturation were not affected, and REV1AA B cells underwent normal activation and class switch recombination. Analysis of Ig gene hypermutation in REV1AA mice revealed a great decrease of C to G and G to C transversions, consistent with the disruption of its deoxycytidyl transferase activity. Intriguingly, REV1AA mice also exhibited a significant reduction of C to T and G to A transitions. Moreover, each type of nucleotide substitutions at A:T base pairs was uniformly reduced in REV1AA mice, a phenotype similar to that observed in mice haploinsufficient for Polh. These results reveal an unexpected role for REV1 in the generation of C:G transitions and A:T mutations and suggest that REV1 is involved in multiple mutagenic pathways through functional interaction with other polymerases during the hypermutation process.

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    Article: The Fanconi anemia core complex is dispensable during somatic hypermutation and class switch recombination.
    Peter H L Krijger, Niek Wit, Paul C M van den Berk, Heinz Jacobs
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    ABSTRACT: To generate high affinity antibodies during an immune response, B cells undergo somatic hypermutation (SHM) of their immunoglobulin genes. Error-prone translesion synthesis (TLS) DNA polymerases have been reported to be responsible for all mutations at template A/T and at least a fraction of G/C transversions. In contrast to A/T mutations which depend on PCNA ubiquitination, it remains unclear how G/C transversions are regulated during SHM. Several lines of evidence indicate a mechanistic link between the Fanconi Anemia (FA) pathway and TLS. To investigate the contribution of the FA pathway in SHM we analyzed FancG-deficient B cells. B cells deficient for FancG, an essential member of the FA core complex, were hypersensitive to treatment with cross-linking agents. However, the frequencies and nucleotide exchange spectra of SHM remained comparable between wild-type and FancG-deficient B cells. These data indicate that the FA pathway is not involved in regulating the outcome of SHM in mammals. In addition, the FA pathway appears dispensable for class switch recombination.
    PLoS ONE 01/2010; 5(12):e15236. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

abasic sites
 
C transversions
 
catalytic activity
 
catalytically inactive REV1
 
functional interaction
 
great decrease
 
hypermutation process
 
Ig gene hypermutation
 
Intriguingly
 
mammalian cells
 
multiple mutagenic pathways
 
nucleotide substitutions
 
phenotype
 
pure C57BL/6 genetic background
 
recombination
 
REV1
 
REV1AA
 
REV1AA B cells
 
REV1AA mice
 
T cell development
 

Keiji Masuda