ATM increases activation-induced cytidine deaminase activity at downstream s regions during class-switch recombination

Lyne Khair, Jeroen E.J. Guikema, Erin K. Linehan, Anna J. Ucher, Niek G.J. Leus, Colin Ogilvie, Zhenkun Lou, Carol E. Schrader, Janet Stavnezer

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Activation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C region genes. DSBs are necessary for CSR, but improper regulation of DSBs can lead to chromosomal translocations that can result in B cell lymphoma. The protein kinase ataxia telangiectasia mutated (ATM) is an important proximal regulator of the DNA damage response (DDR), and translocations involving S regions are increased in its absence. ATM phosphorylates H2AX, which recruits other DNA damage response (DDR) proteins, including mediator of DNA damage checkpoint 1 (Mdc1) and p53 binding protein 1 (53BP1), to sites of DNA damage. As these DDR proteins all function to promote repair and recombination of DSBs during CSR, we examined whether mouse splenic B cells deficient in these proteins would show alterations in S region DSBs when undergoing CSR.We find that in atm1/1 cells Sm DSBs are increased, whereas DSBs in downstream Sg regions are decreased. We also find that mutations in the unrearranged Sg3 segment are reduced in atm1/1 cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm1/1 cells Sm DSBs accumulate as they lack a recombination partner.

Original languageEnglish (US)
Pages (from-to)4887-4896
Number of pages10
JournalJournal of Immunology
Volume192
Issue number10
DOIs
StatePublished - May 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Khair, L., Guikema, J. E. J., Linehan, E. K., Ucher, A. J., Leus, N. G. J., Ogilvie, C., Lou, Z., Schrader, C. E., & Stavnezer, J. (2014). ATM increases activation-induced cytidine deaminase activity at downstream s regions during class-switch recombination. Journal of Immunology, 192(10), 4887-4896. https://doi.org/10.4049/jimmunol.1303481