Modeling human disease in mice; DNA repair and epigenetic reprogramming
Role of AlkB homologs 1 and 7 (ABH1 and 7) in epigenetic reprogramming.
We design gene targeted mice in order to elucidate the role of single genes in tumorgenesis (DNA repair genes) and epigenetic reprogramming/embryo development (histone demethylases). We have successfully (in 2007) completed 5 new models with elucidating exiting new roles of both classes of enzymes.
To assess the role of the mammalian ABH’s in vivo, we design mice lacking individual ABH genes (Ringvoll et al., EMBO j., 2006, 25, 2189–98). In collaboration with the group of Pål Falnes we are designing models and biochemical assays for the remaining six homologs. Mice lacking ABH1, ABH2, ABH3 and ABH8 have now been produced. Furthermore, mABH7 targeting has been verified in ES-clones. This project focuses on epigenetic reprogramming carried out by ABH1 and possible by ABH7. For ABH1, initial biochemical studies are in harmony with the mice studies.
Further, we have succeeded in the production of highly tumor prone mouse models lacking genes involved in resolving secondary structures in DNA generated during repair, replication and recombination processes.
[Nobel Prize for genetic modification]
Tidsskr Nor Laegeforen 2007 Nov;127(23):3054.
Mutations in the RAD27 and SGS1 genes differentially affect the chronological and replicative lifespan of yeast cells growing on glucose and glycerol.
FEMS Yeast Res 2007 Sep;7(6):848-59. Epub 2007 mai 16
OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.
Nature 2007 May;447(7143):447-52. Epub 2007 apr 22
Structural basis for enzymatic excision of N1-methyladenine and N3-methylcytosine from DNA.
EMBO J 2007 Apr;26(8):2206-17. Epub 2007 mar 29
Repeated inhalations of diesel exhaust particles and oxidatively damaged DNA in young oxoguanine DNA glycosylase (OGG1) deficient mice.
Free Radic Res 2007 Feb;41(2):172-81.
Genome instability and DNA damage accumulation in gene-targeted mice.
Neuroscience 2007 Apr;145(4):1309-17. Epub 2007 jan 9
Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice.
Oncogene 2007 Jun;26(27):4044-8. Epub 2007 jan 8
Repair of methyl lesions in DNA and RNA by oxidative demethylation.
Neuroscience 2007 Apr;145(4):1222-32. Epub 2006 des 18
Oxidative damage to purines in DNA: role of mammalian Ogg1.
DNA Repair (Amst) 2007 Apr;6(4):481-8. Epub 2006 nov 28
A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome.
Neuroscience 2007 Apr;145(4):1397-406. Epub 2006 nov 2
Organ and cell specificity of base excision repair mutants in mice.
Mutat Res 2007 Jan;614(1-2):56-68.