BBB seminar: Hans E. Krokan
Genomic uracil – Important carcinogenic lesion, but normal intermediate in adaptive immunity
Hans E. Krokan
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim
DNA was for a long time thought to be a rather inert molecule. However, the ground-breaking work of Tomas Lindahl in the 1970ties revealed that spontaneous decay of DNA takes place at appreciable rates. Common lesions include hydrolytic depurination and base deamination (e.g. cytosine to uracil), as well as various types of DNA damage from reactive oxygen species (ROS). Lindahl also identified enzymes involved in the repair of such lesions, e.g. uracil-DNA glycosylase. Spontaneous damage amounts to at least 20 000 lesions per mammalian genome per day and probably represents the quantitatively dominant source of DNA damage. Base excision repair (BER) is the versatile mechanism that repairs different types of spontaneous DNA base damage, thus preventing mutations. Other pathways process DNA damage caused by physical (e.g. radiation) and chemical agents, although there is considerable overlap between the functions of DNA repair mechanisms.
Importantly, the mechanism of DNA repair shares numerous protein factors with the mechanism of adaptive immunity; including uracil-DNA glycosylase 2 (UNG2). Paradoxically, UNG2 here has a mutagenic function, through its role in somatic hypermutation and class switch recombination, both initiated by activation-induced deaminase (AID). Adaptive immunity is essential, but risky. Thus, it has become apparent that untargeted actions of AID generate U:G mismatches that may contribute to mutations in many common forms of cancer. We have studied the role of AID in adaptive immunity, as well as in the development of B-cell lymphomas. We found that genomic uracil is significantly higher in B-cell lymphoma cell lines compared to non-lymphoma cancer cell lines and normal circulating lymphocytes. The genomic uracil levels were highly correlated with AID expression, but not with expression of other cytosine deaminases (APOBECs). We also observed an inverse correlation of genomic uracil and expression of the uracil-DNA glycosylases UNG and SMUG1. Furthermore, we found that clustered mutations (kataegis) in lymphoma and chronic lymphocytic leukemia predominantly carry AID-hotspot mutational signatures. In conclusion, AID-induced mutagenic U:G mismatches in DNA may be a fundamental and common cause of mutations in B-cell malignancies.
Chairperson: Rein Aasland, Department of Molecular Biology