Activation Induced Deaminase (AID) belongs to the protein family of DNA
deaminases, which catalyse the deamination of the cytosine residues in single
stranded DNA, resulting in the formation of deoxy-uracils. The enzymatic
activity of AID is required for the immunoglobulin gene modifications by class
switch recombination (CSR), somatic hypermutation (SHM) and gene conversion
(iGC). While being essential for antibody diversification, the activity of AID can
be harmful for the organism due to its direct mutagenic activities and induction of
genomic instability.
This thesis investigates AID regulation both, on the level of gene expression
and its interaction partners, and the DNA repair pathways triggered by AIDmediated
DNA deamination. Firstly, I have identified estrogen and progesterone
as regulators of AID expression. This is achieved via direct binding of estrogen
and progesterone receptors to AID promoter. Estrogen leads to an induction of
AID expression and increase in AID-mediated downstream pathways β SHM,
CSR as well as oncogenic translocations between Ig and c-myc loci. In contrast,
progesterone results in a decrease in AID expression and an attenuation of its
downstream pathways. Secondly, by generating DT40 cell lines with
endogenously tagged AID, we used co-immunoprecipitation and subsequent mass
spectrometry for identifying proteins that form a complex with AID in the
cytoplasm, nucleoplasm and chromatin. The results of this approach gave us
possible insight into the mechanistic process of AID-mediated DNA deamination
in vivo, suggesting that chromatin bound AID resides in a complex with
elongating RNA polymerase II. Thirdly, by expressing AID in meiotic
recombination deficient fission yeast and nematode, we have established that a
meiotic cell can process a base mismatch, using the base excision repair
machinery, to give rise to meiotic recombination. This suggests that meiotic cells
can process lesions other than Spo-11 induced DSBs for recombination