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

B-cell lymphomagenesis in Ung-deficient mice: collaboration between chronic antigenic stimulation and DNA repair deficiency

Awarded: NOK 6.4 mill.

The importance of responding appropriately to DNA damage is highlighted by the frequent development of human disease, most notably cancer, in cells where this response is compromised. Here, we ask whether endogenous DNA damage, such as uracil in DNA, can contribute to activation of the DNA damage response (DDR) pathways. Uracil is an inappropriate base in DNA, and it is one of the most common types of endogenous DNA damage, that is, it forms spontaneously independent of an exogenous DNA damaging agent. Se veral lines of research in our laboratory aim to characterise the biological consequences of accumulation of uracil in DNA and to define the cellular responses to such lesions. Here, we will test whether misincorporated uracil is mutagenic in mammalian ce lls. If so, uracil incorporation could, in principle, contribute to both initiation and progression of cancer. We recently showed that misincorporated uracil activated the DDR in Caenorhabditis elegans and described a genetic interaction between the Base Excision Repair pathway and the S-phase cell-cycle checkpoint. This led us to propose that the presence of non-mutagenic and non-cytotoxic DNA damage might contribute to formation of tumours. Here, we will test whether the S-phase checkpoint is also preve nting mutagenesis caused by propagation of repair intermediates arising from processing of misincorporated uracil in mammalian cells. Thus, the present project represents basic research that is expected to make a significant contribution to our understand ing of the role of endogenous DNA damage and repair in the development of cancer. Finally, we present a strategy to show whether and how two different modes of transformation, lack of DNA repair and chronic antigenic stimulation, might work together to gi ve B-cell lymphoma in mice.

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

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