This week we are celebrating one of our CRUK funded scientists Tomas Lindahl, who was recently jointly awarded Nobel prize in Chemistry for“mechanistic studies of DNA repair”.
Tomas Lindahl FRS MedSci is a Swedish scientist specialising in DNA damage and repair. He was director of the Clare Hall Laboratories from 1986-2005. Whilst at Clare Hall, Tomas Lindahl’s laboratory characterised different DNA repair pathways in a long term project to better understanding of the cellular defence mechanisms against damage to the human genome.
Ximbio is privileged to house reagents generated out of key research conducted at Clare Hall. These include:
This mouse model was generated from an in vivo study of UNG knockout and DNA mismatch mutation during DNA synthesis. Results from this study demonstrated the development of spontaneous malignancies in mice due to deficiency in a DNA glycosylase and a specific role for Ung in the immune system, with lymphomagenesis being related to perturbed processing of antibody genes in germinal centre B cells. Mice developed B cell lymphoma and were abnormally defective in their immune response, as described in Oncogene. 2003 Aug 21;22(35):5381-6. There is also a mouse embryonic fibroblasts from this line available.
Mouse embryonic fibroblasts generated from the in vivo study of UNG knockout and DNA mismatch mutation during DNA synthesis.
TREX1, originally designated DNase III, was isolated as a major nuclear DNA-specific 3' -- 5' exonuclease that is widely distributed in both proliferating and non-proliferating mammalian tissues. The Trex1 KO mouse model was created for studies of the human recessive autoimmune disease Aicardi-Goutieres syndrome. This mouse model has potential use for testing of therapeutic agents and identifies a novel immune pathway. There is also a mouse embryonic fibroblasts from this line available.
Mouse embryonic fibroblast cell line demonstrating novel interconnections between DNA replication, DNA damage checkpoint signalling and antiviral-like autoimmune responses Spontaneously transformed mouse embryonic fibroblast (MEF) cell line.
OGG1 defect together with MYH defect causes greatly increased frequency of lung cancer. Knockout mice have been generated deficient in the OGG1 DNA glycosylase that excises the most frequent mutagenic oxidative base lesion, 8-oxoG. Despite this increase in potentially miscoding DNA lesions, OGG1-deficient mice exhibit only a moderately, but significantly, elevated spontaneous mutation rate in non-proliferative tissues, do not develop malignancies, and show no marked pathological changes. Studies using this mouse have shown that:
- 8-oxoG residues accumulate in the genome to substantially increased levels in the non-proliferating liver of ogg1 null mice;
- there is no excision of 8-oxoG initiated by a different DNA glycosylase in cell-free tissue extracts, but there is significant slow repair in an ogg1 null cell line;
- the in vivo spontaneous mutation frequency is increased (2- to 3-fold) in liver but not in more rapidly proliferating testis.
- OGG1 null mice do not show an increased tumor incidence, although inactivating mutations in the OGG1 gene have been documented in a small number of sporadic human lung, kidney, gastric, and head-and-neck tumors.
The cell line can be used to assess the role of the mammalian enzyme OGG1 in repair of DNA damage and prevention of carcinogenesis. The cell line can be used to assess the incidence and consequences of 8-oxoG formation in the mammalian genome.
Some of Lindahls key publications include:
· Lindahl. Instability and decay of the primary structure of DNA.Nature362, 709-715 (1993)
· Lindahl and R.D. Wood. Quality control by DNA repair.Science286, 1897-1905 (1999)
· Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.Nature. 2002;419: 174-178
· Barnes DE and Lindahl T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells.Annu. Rev. Genet. 2004;38:445-476
· Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.Cell. 2007;131:873-886
View a video of Tomas Lindahl and learn more about his work.
HAVE YOU REGISTERED?
Join theever-growing global Ximbio community.Register and receive updates about new reagents, institutes and new featuresbeing added to the website.