DNA-dependent protein kinase inhibits AID-induced antibody gene conversion

Adam J.L. Cook, Joanna M. Raftery, K. K.Edwin Lau, Andrew Jessup, Reuben S. Harris, Shunichi Takeda, Christopher J. Jolly

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Affinity maturation and class switching of antibodies requires activation-induced cytidine deaminase (AID)-dependent hypermutation of Ig V(D)J rearrangements and Ig S regions, respectively, in activated B cells. AID deaminates deoxycytidine bases in Ig genes, converting them into deoxyuridines. In V(D)J regions, subsequent excision of the deaminated bases by uracil-DNA glycosylase, or by mismatch repair, leads to further point mutation or gene conversion, depending on the species. In Ig S regions, nicking at the abasic sites produced by AID and uracil-DNA glycosylases results in staggered double-strand breaks, whose repair by nonhomologous end joining mediates Ig class switching. We have tested whether nonhomologous end joining also plays a role in V(D)J hypermutation using chicken DT40 cells deficient for Ku70 or the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inactivation of the Ku70 or DNA-PKcs genes in DT40 cells elevated the rate of AID-induced gene conversion as much as 5-fold. Furthermore, DNA-PKcs-deficiency appeared to reduce point mutation. The data provide strong evidence that double-strand DNA ends capable of recruiting the DNA-dependent protein kinase complex are important intermediates in Ig V gene conversion.

Original languageEnglish (US)
Pages (from-to)792-799
Number of pages8
JournalPLoS biology
Volume5
Issue number4
DOIs
StatePublished - Apr 2007

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