Tomas Lindahl : Mutagenesis

Cancer therapy often involves treatment with cytotoxic drugs and/or ionizing radiation. The potentially toxic DNA lesions induced can be counteracted and corrected by cellular DNA repair mechanisms. Consequently, DNA repair enzymes might be promising targets for anticancer drugs that could be used to enhance the biological effects of cytotoxic agents.

The Mutagenesis Laboratory characterised different DNA repair pathways in a long-term project, to provide better understanding of the cellular defence mechanisms against damage to the human genome.

Damaged sites in the chromosomal DNA can result in cell death or cancer, but may be corrected by DNA repair enzymes prior to phenotypic expression. The properties of several nuclear enzymes that remove harmful lesions or local aberrant structures from DNA have been investigated. The absence of such DNA repair factors may result in an increased frequency of malignant transformation, or in some cases may be detected as immunological deficiencies.

Tomas closed his lab at the Clare Hall laboratories in 2009 but remains an Emeritus Group Leader. (email:tomas.lindahl@cancer.org.uk)

Significant LRI Papers

• 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 (Abstract)

• Barnes DE and Lindahl T.  Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu. Rev. Genet. 2004;38:445-476 (Abstract)

• Gerken T, Girard CA, Tung YCL, Webby CJ, Saudek V, Hewitson KS, Yeo GSH, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O’Rahilly S, Schofield CJ. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469-1472 (Abstract)

• Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007;131:873-886 (Abstract)

• Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Kletter J, Livingston JH, Lynch SA, Massey FR, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P,  Bonthron DT, Jackson AP, Barnes DE Lindahl T. Mutations in the gene encoding the 3’ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nature Genetics. 2006;38:917-920 (Abstract)