MBD4 Facilitates Immunoglobulin Class Switch Recombination.

Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1).

AID hits the jackpot when missing the target.

Activation induced deaminase is the single B cell specific factor mediating class switch recombination and somatic hypermutation. Numerous studies have shown that AID preferentially targets Ig substrates and also attacks non-Ig substrates to create DNA damage that contributes to lymphomagenesis. AID targeting to Ig loci is linked to transcription but the mechanism governing this process has been obscure.

Adenovirus E1B 19-kilodalton protein modulates innate immunity through apoptotic mimicry.

Unlabelled: Cells that undergo apoptosis in response to chemical or physical stimuli repress inflammatory reactions, but cells that undergo nonapoptotic death in response to such stimuli lack this activity. Whether cells dying from viral infection exhibit a cell death-type modulatory effect on inflammatory reactions is unknown. We compared the effects on macrophage inflammatory responses of cells dying an apoptotic or a nonapoptotic death as a result of adenoviral infection.

Complex relationship between mismatch repair proteins and MBD4 during immunoglobulin class switch recombination.

Mismatch repair (MMR) safeguards against genomic instability and is required for efficient Ig class switch recombination (CSR). Methyl CpG binding domain protein 4 (MBD4) binds to MutL homologue 1 (MLH1) and controls the post-transcriptional level of several MMR proteins, including MutS homologue 2 (MSH2). We show that in WT B cells activated for CSR, MBD4 is induced and interacts with MMR proteins, thereby implying a role for MBD4 in CSR.