Background and activities
DNA repair and adaptive immunity
How is DNA lesions generated and repaired in our genome? What is the molecular link between DNA repair and adaptive immunity? What goes wrong when normal cells accumulate mutations and are converted to cancer cells? These are important questions in my research.
I have for many years worked within the field of DNA repair and genome stability with specific focus on repair of genomic uracil (deaminated cytosine). The work includes structural and functional characterization of the uracil-DNA glycosylases UNG and SMUG1 (Biochemistry 1995; Cell 1995; Nature 1996; Embo J 1996, 2000, 2008; JBC 2002; NAR 2007, 2011; JBC 2011: DNA repair 2012).
Studies of immune-deficient patients with mutations in the UNG gene revealed an essential role of this enzyme also in adaptive immunity (Nature Immunology 2003; JEM 2005). Here, the UNG glycosylase plays a central role in processing of enzymatically introduced uracil at the Ig loci to achieve affinity maturation of antibodies.
The primary and physiologically role of activation-induced cytidine deaminase (AID), the master enzyme in adaptive immunity, is to introduce uracil lesions at the Ig loci to initiate antibody diversification.
However, AID and other members of this mutator-protein family (APOBECs) pose a great threat to genomic integrity and mistargeted AID activity is likely a major cause behind oncogenic mutations and translocations in B-cell lymphomas as well as other cancers. Understanding regulation of these dynamic genome processes has during the last years become my major research interest (Nat Struct Mol Biol 2009; JMB 2013; Exp Cell Research 2014; DNA repair 2015).
Scientific, academic and artistic work
A selection of recent journal publications, artistic productions, books, including book and report excerpts. See all publications in the database
- (2015) AID expression in B-cell lymphomas causes accumulation of genomic uracil and a distinct AID mutational signature. DNA Repair. vol. 25.
- (2014) Activation-induced cytidine deaminase (AID) is localized to subnuclear domains enriched in splicing factors. Experimental Cell Research. vol. 322 (1).
- (2014) Error-free versus mutagenic processing of genomic uracil-Relevance to cancer. DNA Repair. vol. 19.
- (2014) Expression and recruitment of uracil-DNA glycosylase are regulated by E2A during antibody diversification. Molecular Immunology. vol. 60 (1).
- (2013) A combined nuclear and nucleolar localization motif in activation-induced cytidine deaminase (AID) controls immunoglobulin class switching. Journal of Molecular Biology. vol. 425 (2).
- (2013) Genomic uracil - potent mutagen but normal intermediate in adaptive immunity. The FEBS Journal. vol. 280.
- (2012) Strikingly different properties of uracil-DNA glycosylases UNG2 and SMUG1 may explain divergent roles in processing of genomic uracil. DNA Repair. vol. 11 (6).
- (2012) The UNG2 Arg88Cys variant abrogates RPA-mediated recruitment of UNG2 to single-stranded DNA. DNA Repair. vol. 11 (6).
- (2011) Uracil-DNA Glycosylase in Base Excision Repair and Adaptive Immunity: SPECIES DIFFERENCES BETWEEN MAN AND MOUSE. Journal of Biological Chemistry. vol. 286 (19).
- (2011) UNG-initiated base excision repair is the major repair route for 5-fluorouracil in DNA, but 5-fluorouracil cytotoxicity depends mainly on RNA incorporation. Nucleic Acids Research. vol. 39 (19).
- (2010) DNA repair and cancer. European Journal of Cancer. vol. 8 (5).
- (2009) Active nuclear import and cytoplasmic retention of activation-induced deaminase. Nature Structural & Molecular Biology. vol. 16 (5).
- (2009) Uracil in DNA and its processing by different DNA glycosylases. Philosophical Transactions of the Royal Society of London. Biological Sciences. vol. 364 (1517).
- (2008) Cell cycle-specific UNG2 phosphorylations regulate protein turnover, activity and association with RPA. EMBO Journal. vol. 27 (1).
- (2008) Human AlkB homolog 1 is a mitochondrial protein that demethylates 3-methylcytosine in DNA and RNA. Journal of Biological Chemistry. vol. 238 (36).
- (2007) Uracil in DNA - General mutagen, but normal intermediate in acquired immunity. DNA Repair.
- (2007) Repair og uracil in DNA by UNG2 and SMUG1 - an update. DNA Repair.
- (2007) NEIL1 is the major DNA glycosylase that processes 5-hydroxyuracil in the proximity of a DNA single-strand break. Biochemistry. vol. 46 (13).
- (2007) Uracil-DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms. Nucleic Acids Research. vol. 35 (12).
- (2006) Genomic uracil and human disease. Experimental Cell Research. vol. 312.