Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination.
Immunoglobulin class-switch recombination (CSR) requires activation-induced cytidine deaminase (AID). Deamination of DNA by AID in transcribed switch (S) regions leads to double-stranded breaks in DNA that serve as obligatory CSR intermediates. Here we demonstrate that the catalytic and regulatory subunits of protein kinase A (PKA) were specifically recruited to S regions to promote the localized phosphorylation of AID, which led to binding of replication protein A and subsequent propagation of the CSR cascade. Accordingly, inactivation of PKA resulted in considerable disruption of CSR because of decreased AID phosphorylation and recruitment of replication protein A to S regions. We propose that PKA nucleates the formation of active AID complexes specifically on S regions to generate the high density of DNA lesions required for CSR.
Vuong
Bao Q
BQ
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Lee
Mieun
M
Kabir
Shaheen
S
Irimia
Cristina
C
Macchiarulo
Stephania
S
McKnight
G Stanley
GS
Chaudhuri
Jayanta
J
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000276:immunology*; D003564:Cytidine Deaminase / Q000276:immunology*; D053903:DNA Breaks, Double-Stranded; D017578:Immunoglobulin Class Switching; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011485:Protein Binding; D011995:Recombination, Genetic / Q000276:immunology*; D051716:Replication Protein A / Q000276:immunology*; D012192:Retroviridae Infections / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D051716:Replication Protein A; D017868:Cyclic AMP-Dependent Protein Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase