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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Base excision repair proteins in DNA repair and early steps of adaptive immunity

Tildelt: kr 5,3 mill.

DNA is continuously damaged by cellular and environmental agents. Five main DNA repair pathways correct such lesions. These are important in cancer prevention, but surprisingly, also for adaptive immunity. Our research group concentrates on base excision repair (BER) and direct repair of damage. BER correct lesions causing minor helix distortions, such as uracil, certain alkylations and oxidation damage to bases. Direct repair mechanisms include direct repair of some alkylation lesions that are not repair ed by BER, newcomers in this field are human homologues of bacterial AlkB. Some of these are genuine DNA repair proteins, while others seem to be involved in modifications of macromolecules, e.g. tRNA. Generally, DNA must be repaired prior to replication to prevent mutations, but DNA damage is also cytotoxic and must therefore be repaired in non-proliferating cells as well. We will examine further molecular mechanisms of BER and direct base repair, and the roles of BER proteins and activation induced deam inase (AID) in early steps of adaptive immunity. We will use purified proteins and complexes to examine structure-function relationships and human and mouse cell lines, as well as mouse models deficient in DNA repair protein(s), to examine functions and d ysfunctions using a number of different assays. We will also examine roles of uracil-DNA glycosylases UNG1 and 2, SMUG1 and T(U)-mismatch glycosylase in initial steps of BER in different states of proliferation, regulation of UNG2 at mRNA level, significa nce of protein-protein interactions for efficiency and fidelity of BER and potential role of DNA glycosylases in sensitivity to 5-FU. We will examine roles of AlkB holologues in nucleic acid repair and modification. Finally, we will examine roles of UNG2, AID and proteins with which they interact in B-cells in early steps in adaptive immunity (somatic hypermutation and class switch recombination), and mechanisms of development of hyperplasia due to UNG2 deficiency.


FRIMEDBIO-Fri prosj.st. med.,helse,biol