Alkyladenine DNA glycosylase (Aag) in somatic hypermutation and class switch recombination

• Published in: DNA repair 2007-12, Vol.6 (12), p.1764-1773
• Main Authors: Longerich, Simonne, Meira, Lisiane, Shah, Dharini, Samson, Leona D., Storb, Ursula
• Format: Article
• Language: English
• Subjects: Alkyladenine DNA glycosylase; Animals; Bacteriology; Base Sequence; Biological and medical sciences; Class switch recombination; DNA Primers; Fundamental and applied biological sciences. Psychology; Genic rearrangement. Recombination. Transposable element; Growth, nutrition, cell differenciation; Immunoglobulin genes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Molecular and cellular biology; Molecular genetics; Mutagenesis. Repair; Mutation; N-Glycosyl Hydrolases - genetics; N-Glycosyl Hydrolases - metabolism; Recombination, Genetic; Somatic hypermutation
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2007.06.012

Somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin ( Ig) genes require the cytosine deaminase AID, which deaminates cytosine to uracil in Ig gene DNA. Paradoxically, proteins involved normally in error-free base excision repair and mismatch repair, seem to be co-opted to facilitate SHM and CSR, by recruiting error-prone translesion polymerases to DNA sequences containing deoxy-uracils created by AID. Major evidence supports at least one mechanism whereby the uracil glycosylase Ung removes AID-generated uracils creating abasic sites which may be used either as uninformative templates for DNA synthesis, or processed to nicks and gaps that prime error-prone DNA synthesis. We investigated the possibility that deamination at adenines also initiates SHM. Adenosine deamination would generate hypoxanthine (Hx), a substrate for the alkyladenine DNA glycosylase (Aag). Aag would generate abasic sites which then are subject to error-prone repair as above for AID-deaminated cytosine processed by Ung. If the action of an adenosine deaminase followed by Aag were responsible for significant numbers of mutations at A, we would find a preponderance of A:T > G:C transition mutations during SHM in an Aag deleted background. However, this was not observed and we found that the frequencies of SHM and CSR were not significantly altered in Aag −/− mice. Paradoxically, we found that Aag is expressed in B lymphocytes undergoing SHM and CSR and that its activity is upregulated in activated B cells . Moreover, we did find a statistically significant, albeit low increase of T:A > C:G transition mutations in Aag −/− animals, suggesting that Aag may be involved in creating the SHM A > T bias seen in wild type mice.