Abstracts (poster) - Wissenschaft Online

Svend Petersen-Mahrt, Wolf Reik, Siim Pauklin, Heather Coker
Epigenetic Reprogramming of 5-meC via DNA Deamination and
DNA Repair
Activation-induced cytidine deaminase (AID) coordinates B-cell class switch
recombination and somatic hypermutation, to diversify the expressed immunoglobulin
repertoire of a healthy immune system. Activity of AID at the immunoglobulin locus has
been confirmed by the presence of uracil, the product of AID mediated cytosine
deamination. Other forms of cytosine have not previously been thought to be significant
substrates, however we have demonstrated that in vitro and in E. coli 5’-methyl cytosine
(5’me-C), an important element within epigenetic regulation, is also deaminated by AID.
Such activity results in conversion of 5’me-C to thymine with subsequent repair of the
T:G mismatch not reinstating the methyl cytosine, thus potentially altering the gene’s
epigenetics status. Furthermore, AID is co-expressed with a surrounding cluster of
pluripotency genes during early development, linking expression to function. The
analysis has now been extended to in vivo mouse transgenics. We are able to show that
AID, if targeted to a methylated locus can actively (depending on the catalytic activity of
AID) initiate epigenetic reprogramming. Our current work focuses on the molecular
mechanism on how AID and other DNA deaminases can initiate and process the lesions
at 5’me-C sites in DNA. By comparing and contrasting the different cell milieus for
immunoglobulin diversification and epigenetic reprogramming, as well as identify AID
interacting proteins, our current model states, that AID can alter the balance of the DNA
repair pathways and lead to mutagenic or non-mutagenic repair depending on the status
of the cell.
contact:
Dr Svend Petersen-Mahrt
Cancer Research UK
DNA Editing - Clare Hall Laboratories
skpm@cancer.org.uk
Balnche Lane
EN6 3LD South Mimms (UK)