ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination.
J Immunol
; 192(10): 4887-96, 2014 May 15.
Article
in En
| MEDLINE
| ID: mdl-24729610
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Rearrangement, B-Lymphocyte
/
Cytidine Deaminase
Limits:
Animals
Language:
En
Journal:
J Immunol
Year:
2014
Type:
Article