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DNA breaks in immunoglobulin Class Switch Recombination that depend on UNG but not AID
Author(s) -
Max Edward E.,
Arudchandran Arulvathani,
Bernstein Ralph M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.849.2
Subject(s) - immunoglobulin class switching , uracil dna glycosylase , cytosine deaminase , cytosine , dna , cytidine deaminase , biology , microbiology and biotechnology , gene , genetics , dna glycosylase , dna repair , antibody , b cell , genetic enhancement
B lymphocytes switch from secreting IgM to secreting IgG, IgA or IgE through a DNA recombination, Class Switch Recombination. CSR is thought to be triggered by Activation Induced Deaminase (AID), which is believed to deaminate cytosines to uracil in Switch region DNA. Excision of uracils by uracil DNA glycosylase (product of the UNG gene) generates abasic sites, which are targeted for the DNA cleavage required for CSR. Consistent with this model, CSR‐related double‐strand breaks (dsbs) – detected by Ligation Mediated PCR (LMPCR) ‐‐ have been reported to be dramatically reduced in either AID−/− or UNG−/− B‐cells. Here we examine single‐strand breaks (ssbs) using LMPCR and report, surprisingly, that CSR‐related antisense‐strand breaks in Sμ and Sγ regions are dependent on UNG but not AID, suggesting participation of a cytosine deaminase other than AID. This conclusion is supported by the sequences at these DNA breaks, which show a bias for a consensus sequence different from that reported for AID. The ssbs appear to be part of the normal CSR pathway, since in B cells in which CSR is blocked by deletion of Sμ, the content of Sγ ssbs is elevated, as though ssbs persist in the absence of a recombination partner for completing μ‐to‐γ CSR. These results suggest a narrower role for AID in CSR than previously recognized, and prompt a search for a putative alternative cytosine deaminase participating in CSR. Supported by FDA funds.