ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination
Guikema, Jeroen E. J.
Linehan, Erin K.
Ucher, Anna J.
Leus, Niek G.J.
Schrader, Carol E.
UMass Chan AffiliationsDepartment of Microbiology and Physiological Systems
Document TypeJournal Article
Ataxia Telangiectasia Mutated Proteins
Chromosomal Proteins, Non-Histone
Gene Rearrangement, B-Lymphocyte
Intracellular Signaling Peptides and Proteins
Genetics and Genomics
Immunology and Infectious Disease
MetadataShow full item record
AbstractActivation-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 atm(-/-) cells Smu DSBs are increased, whereas DSBs in downstream Sgamma regions are decreased. We also find that mutations in the unrearranged Sgamma3 segment are reduced in atm(-/-) cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm(-/-) cells Smu DSBs accumulate as they lack a recombination partner.
SourceJ Immunol. 2014 May 15;192(10):4887-96. doi: 10.4049/jimmunol.1303481. Epub 2014 Apr 11. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/30428
Related ResourcesLink to Article in PubMed