Uracil excision by endogenous SMUG1 glycosylase promotes efficient Ig class switching and impacts on A:T substitutions during somatic mutation

Download
  1. Get@NRC: Uracil excision by endogenous SMUG1 glycosylase promotes efficient Ig class switching and impacts on A:T substitutions during somatic mutation (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1002/eji.201444482
AuthorSearch for: ; Search for: ; Search for: ; Search for:
TypeArticle
Journal titleEuropean Journal of Immunology
ISSN0014-2980
Volume44
Issue7
Pages19251935; # of pages: 11
SubjectClass switching; DNA deamination; Somatic hypermutation; Uracil; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Mice; Mutation; MutS Homolog 2 Protein; Uracil; Uracil-DNA Glycosidase
AbstractExcision of uracil introduced into the immunoglobulin loci by AID is central to antibody diversification. While predominantly carried out by the UNG uracil-DNA glycosylase as reflected by deficiency in immunoglobulin class switching in Ung-/- mice, the deficiency is incomplete, as evidenced by the emergence of switched IgG in the serum of Ung-/- mice. Lack of switching in mice deficient in both UNG and MSH2 suggested that mismatch repair initiated a backup pathway. We now show that most of the residual class switching in Ung-/- mice depends upon the endogenous SMUG1 uracil-DNA glycosylase, with in vitro switching to IgG1 as well as serum IgG3, IgG2b, and IgA greatly diminished in Ung-/-Smug1-/- mice, and that Smug1 partially compensates for Ung deficiency over time. Nonetheless, using a highly MSH2-dependent mechanism, Ung-/-Smug1-/- mice can still produce detectable levels of switched isotypes, especially IgG1. While not affecting the pattern of base substitutions, SMUG1 deficiency in an Ung-/- background further reduces somatic hypermutation at A:T base pairs. Our data reveal an essential requirement for uracil excision in class switching and in facilitating noncanonical mismatch repair for the A:T phase of hypermutation presumably by creating nicks near the U:G lesion recognized by MSH2.
Publication date
PublisherWiley
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); Human Health Therapeutics
Peer reviewedYes
NPARC number21272960
Export citationExport as RIS
Report a correctionReport a correction
Record identifieraee6faa5-6f06-4477-9c6e-4dc573dfc958
Record created2014-12-03
Record modified2016-05-09
Bookmark and share
  • Share this page with Facebook (Opens in a new window)
  • Share this page with Twitter (Opens in a new window)
  • Share this page with Google+ (Opens in a new window)
  • Share this page with Delicious (Opens in a new window)