Title |
ATM Increases Activation-Induced Cytidine Deaminase Activity at Downstream S Regions during Class-Switch Recombination
|
---|---|
Published in |
The Journal of Immunology, May 2014
|
DOI | 10.4049/jimmunol.1303481 |
Pubmed ID | |
Authors |
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 |
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 atm(-/-) cells Sμ DSBs are increased, whereas DSBs in downstream Sγ regions are decreased. We also find that mutations in the unrearranged Sγ3 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 Sμ DSBs accumulate as they lack a recombination partner. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 3% |
Unknown | 30 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 9 | 29% |
Researcher | 8 | 26% |
Professor > Associate Professor | 2 | 6% |
Student > Master | 2 | 6% |
Student > Bachelor | 1 | 3% |
Other | 4 | 13% |
Unknown | 5 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 13 | 42% |
Biochemistry, Genetics and Molecular Biology | 11 | 35% |
Immunology and Microbiology | 2 | 6% |
Unknown | 5 | 16% |