Tomas Lindahl

Publications (35)312.56 Total impact

• Article: Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease.

  Tomas Lindahl, Deborah E Barnes, Yun-Gui Yang, Peter Robins
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  ABSTRACT: The major DNA-specific 3'-5' exonuclease of mammalian cells is TREX1 (3' repair exonuclease 1; previously called DNase III). The human enzyme is encoded by a single exon and, like many 3' exonucleases, exists as a homodimer. TREX1 degrades ssDNA (single-stranded DNA) more efficiently than dsDNA (double-stranded DNA), and its catalytic properties are similar to those of Escherichia coli exonuclease X. However, TREX1 is only found in mammals and has an extended C-terminal domain containing a leucine-rich sequence required for its association with the endoplasmic reticulum. In normal S-phase and also in response to genotoxic stress, TREX1 at least partly redistributes to the cell nucleus. In a collaborative project, we have demonstrated TREX1 enzyme deficiency in Aicardi-Goutières syndrome. Subsequently, we have shown that AGS1 cells exhibit chronic ATM (ataxia telangiectasia mutated)-dependent checkpoint activation, and these TREX1-deficient cells accumulate ssDNA fragments of a distinct size generated during DNA replication. Other groups have shown that the syndromes of familial chilblain lupus as well as systemic lupus erythematosus, and the distinct neurovascular disorder retinal vasculopathy with cerebral leukodystrophy, can be caused by dominant mutations at different sites within the TREX1 gene.
  Biochemical Society Transactions 07/2009; 37(Pt 3):535-8. · 3.71 Impact Factor
• Source

  Available from: Vladimir Saudek

  Article: Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations.

  Sarah Boissel, Orit Reish, Karine Proulx, Hiroko Kawagoe-Takaki, Barbara Sedgwick, Giles S H Yeo, David Meyre, Christelle Golzio, Florence Molinari, Noman Kadhom, Heather C Etchevers, Vladimir Saudek, I Sadaf Farooqi, Philippe Froguel, Tomas Lindahl, Stephen O'Rahilly, Arnold Munnich, Laurence Colleaux
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  ABSTRACT: FTO is a nuclear protein belonging to the AlkB-related non-haem iron- and 2-oxoglutarate-dependent dioxygenase family. Although polymorphisms within the first intron of the FTO gene have been associated with obesity, the physiological role of FTO remains unknown. Here we show that a R316Q mutation, inactivating FTO enzymatic activity, is responsible for an autosomal-recessive lethal syndrome. Cultured skin fibroblasts from affected subjects showed impaired proliferation and accelerated senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.
  The American Journal of Human Genetics 07/2009; 85(1):106-11. · 10.60 Impact Factor
• Article: Preface.

  Patricia J Gearhart, Tomas Lindahl, Michael S Neuberger
  Philosophical Transactions of The Royal Society B Biological Sciences 12/2008; 364(1517):561-2. · 6.40 Impact Factor
• Source

  Available from: aicardi-goutieres.org

  Article: Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.

  Yun-Gui Yang, Tomas Lindahl, Deborah E Barnes
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  ABSTRACT: Trex1 is the major 3' DNA exonuclease in mammalian cells, and mutations in the human TREX1 gene can cause Aicardi-Goutières syndrome, characterized by perturbed immunity. Similarly, Trex1(-/-) mice have an autoinflammatory phenotype; however, the mechanism of Trex1-deficient disease is unknown. We report that Trex1, ordinarily associated with the endoplasmic reticulum (ER), relocalizes to the S phase nucleus after gamma irradiation or hydroxyurea treatment. Notably, Trex1-deficient cells show defective G1/S transition and chronic ATM-dependent checkpoint activation, even in the absence of exogenous stress, correlating with persistent single-stranded DNA molecules produced in S phase, which accumulate in the ER. Our data indicate that Trex1 acts on a single-stranded DNA polynucleotide species generated from processing of aberrant replication intermediates to attenuate DNA damage checkpoint signaling and prevent pathological immune activation.
  Cell 12/2007; 131(5):873-86. · 32.40 Impact Factor
• Source

  Available from: Vladimir Saudek

  Article: The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

  Thomas Gerken, Christophe A Girard, Yi-Chun Loraine Tung, Celia J Webby, Vladimir Saudek, Kirsty S Hewitson, Giles S H Yeo, Michael A McDonough, Sharon Cunliffe, Luke A McNeill, [......], Marcella Ma, Zorica Jovanovic, I Sadaf Farooqi, Barbara Sedgwick, Inês Barroso, Tomas Lindahl, Chris P Ponting, Frances M Ashcroft, Stephen O'Rahilly, Christopher J Schofield
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  ABSTRACT: Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
  Science 12/2007; 318(5855):1469-72. · 31.20 Impact Factor
• Chapter: Repair and Processing Events at DNA Ends

  Tomas Lindahl, Deborah E. Barnes, Arne Klungland, Victoria J. Mackenney, Primo Schär
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  ABSTRACT: Cell nuclei contain several abundant enzymes that bind rapidly and avidly to exposed termini of DNA. The properties and physiological roles of such factors are described; they include poly (ADP-ribose) polymerase, DNA-dependent protein kinase, several DNA ligases and excision–repair enzymes. Telomeres normally seem shielded from these activities by telomere-binding proteins. If incomplete protection of telomeres occurred, the functions of the DNA end-specific enzymes would be relevant for processing of telomeres. This could include alternative pathways for telomerc propagation in telomerase-negative cells.
  09/2007: pages 198 - 208; , ISBN: 9780470515433
• Article: Repair of alkylated DNA: recent advances.

  Barbara Sedgwick, Paul A Bates, Johanna Paik, Susan C Jacobs, Tomas Lindahl
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  ABSTRACT: Cytotoxic and mutagenic methylated bases in DNA can be generated by endogenous and environmental alkylating agents. Such damaged bases are removed by three distinct strategies. The abundant toxic lesion 3-methyladenine (3-alkyladenine) is excised by a specific DNA glycosylase that initiates a base excision-repair process. The toxic lesions 1-methyladenine and 3-methylcytosine are corrected by oxidative DNA demethylation catalyzed by DNA dioxygenases. These enzymes release the methyl moiety as formaldehyde, directly reversing the base damage. The third strategy involves the mutagenic and cytotoxic lesion O(6)-methylguanine which is also repaired by direct reversal but uses a different mechanism. Here, the methyl group is transferred from the lesion to a specific cysteine residue within the methyltransferase itself. In this review, we briefly describe endogenous alkylating agents and the extensively investigated DNA repair enzymes, mammalian 3-methyladenine-DNA glycosylase and O(6)-methylguanine-DNA methyltransferase. We provide a more detailed description of the structures and biochemical properties of the recently discovered DNA dioxygenases.
  DNA Repair 05/2007; 6(4):429-42. · 4.14 Impact Factor
• Article: Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.

  Gillian Rice, William G Newman, John Dean, Teresa Patrick, Rekha Parmar, Kim Flintoff, Peter Robins, Scott Harvey, Thomas Hollis, Ann O'Hara, Ariane L Herrick, Andrew P Bowden, Fred W Perrino, Tomas Lindahl, Deborah E Barnes, Yanick J Crow
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  ABSTRACT: TREX1 constitutes the major 3'-->5' DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.
  The American Journal of Human Genetics 04/2007; 80(4):811-5. · 10.60 Impact Factor
• Article: 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity.

  Qian An, Peter Robins, Tomas Lindahl, Deborah E Barnes
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  ABSTRACT: 5-Fluorouracil (FU) has been widely used for more than four decades in the treatment of a range of common cancers. The fluorine-substituted uracil analogue is converted to several active metabolites but the mechanism of cytotoxicity has remained unclear. In a widely cited but unsubstantiated model, FU is thought to kill cells via the inhibition of thymidylate synthase and increased use of dUTP in place of TTP during DNA replication, with subsequent excision of high levels of uracil causing the fragmentation of newly synthesized DNA. Using gene-targeted cell lines defective in one or both of the two mammalian uracil-DNA glycosylase repair enzymes, we were able to test this model of FU cytotoxicity. Here, we show that incorporation of FU itself into DNA has been previously underestimated and is a predominant cause of cytotoxicity. FU readily becomes incorporated into the DNA of drug-treated cells, and accumulation of FU in the genome, rather than uracil excision, is correlated with FU cytotoxicity in mammalian cells. Furthermore, the Smug1, but not the Ung, uracil-DNA glycosylase excises FU from DNA and protects against cell killing. The data provides a clearer understanding of the action of FU, suggesting predictive biomarkers of drug response and a mechanism for acquired resistance in tumors.
  Cancer Research 03/2007; 67(3):940-5. · 7.86 Impact Factor
• Article: Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

  Yanick J Crow, Bruce E Hayward, Rekha Parmar, Peter Robins, Andrea Leitch, Manir Ali, Deborah N Black, Hans van Bokhoven, Han G Brunner, Ben C Hamel, [......], Roger F Massey, Jean François Meritet, Jacques L Michaud, Gerard Ponsot, Thomas Voit, Pierre Lebon, David T Bonthron, Andrew P Jackson, Deborah E Barnes, Tomas Lindahl
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  ABSTRACT: Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.
  Nature Genetics 08/2006; 38(8):917-20. · 35.53 Impact Factor
• Article: Mutations in the gene encoding the 3|[prime]|-5|[prime]| DNA exonuclease TREX1 cause Aicardi-Gouti|[egrave]|res syndrome at the AGS1 locus

  Yanick J Crow, Bruce E Hayward, Rekha Parmar, Peter Robins, Andrea Leitch, Manir Ali, Deborah N Black, Hans van Bokhoven, Han G Brunner, Ben C Hamel, [......], Roger F Massey, Jean Fran|[ccedil]|ois Meritet, Jacques L Michaud, Gerard Ponsot, Thomas Voit, Pierre Lebon, David T Bonthron, Andrew P Jackson, Deborah E Barnes, Tomas Lindahl
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  ABSTRACT: Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection1, 2. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype3. Here, we show that TREX1, encoding the major mammalian 3' 5' DNA exonuclease4, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1 -/- mouse leads to an inflammatory phenotype5. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.
  Nature Genetics. 07/2006; 38(8):917-920.
• Article: Direct removal of alkylation damage from DNA by AlkB and related DNA dioxygenases.

  Barbara Sedgwick, Peter Robins, Tomas Lindahl
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  ABSTRACT: The cytotoxic alkylation lesions 1-methyladenine (1-alkyladenine) and 3-methylcytosine are removed efficiently from DNA by direct damage reversal, catalyzed by the Escherichia coli AlkB protein and its human homologs ABH2 and ABH3. The enzymes act by oxidative demethylation, employing Fe(II) and alpha-ketoglutarate as cofactors, and release the methyl moiety as formaldehyde. The isolation of these enzymes from overproducing cells is described, as well as the preparation of radioactively labeled substrates and procedures for enzyme assays. Functionality in vivo is examined by complementation of the low survival of alkylated single-stranded DNA bacteriophage in an E. coli alkB mutant.
  Methods in Enzymology 02/2006; 408:108-20. · 2.04 Impact Factor
• Article: Sensitization of human carcinoma cells to alkylating agents by small interfering RNA suppression of 3-alkyladenine-DNA glycosylase.

  Johanna Paik, Tod Duncan, Tomas Lindahl, Barbara Sedgwick
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  ABSTRACT: One of the major cytotoxic lesions generated by alkylating agents is DNA 3-alkyladenine, which can be excised by 3-alkyladenine DNA glycosylase (AAG). Inhibition of AAG may therefore result in increased cellular sensitivity to chemotherapeutic alkylating agents. To investigate this possibility, we have examined the role of AAG in protecting human tumor cells against such agents. Plasmids that express small interfering RNAs targeted to two different regions of AAG mRNA were transfected into HeLa cervical carcinoma cells and A2780-SCA ovarian carcinoma cells. Stable derivatives of both cell types with low AAG protein levels were sensitized to alkylating agents. Two HeLa cell lines with AAG protein levels reduced by at least 80% to 90% displayed a 5- to 10-fold increase in sensitivity to methyl methanesulfonate, N-methyl-N-nitrosourea, and the chemotherapeutic drugs temozolomide and 1,3-bis(2-chloroethyl)-1-nitrosourea. These cells showed no increase in sensitivity to UV light or ionizing radiation. After treatment with methyl methanesulfonate, AAG knockdown HeLa cells were delayed in S phase but accumulated in G2-M. Our data support the hypothesis that ablation of AAG activity in human tumor cells may provide a useful strategy to enhance the efficacy of current chemotherapeutic regimens that include alkylating agents.
  Cancer Research 12/2005; 65(22):10472-7. · 7.86 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: C --> T mutagenesis and gamma-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases.

  Qian An, Peter Robins, Tomas Lindahl, Deborah E Barnes
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  ABSTRACT: The most common genetic change in aerobic organisms is a C:G to T:A mutation. C --> T transitions can arise through spontaneous hydrolytic deamination of cytosine to give a miscoding uracil residue. This is also a frequent DNA lesion induced by oxidative damage, through exposure to agents such as ionizing radiation, or from endogenous sources that are implicated in the aetiology of degenerative diseases, ageing and cancer. The Ung and Smug1 enzymes excise uracil from DNA to effect repair in mammalian cells, and gene-targeted Ung(-/-) mice exhibit a moderate increase in genome-wide spontaneous mutagenesis. Here, we report that stable siRNA-mediated silencing of Smug1 in mouse embryo fibroblasts also generates a mutator phenotype. However, an additive 10-fold increase in spontaneous C:G to T:A transitions in cells deficient in both Smug1 and Ung demonstrates that these enzymes have distinct and nonredundant roles in suppressing C --> T mutability at non-CpG sites. Such cells are also hypersensitive to ionizing radiation, and reveal a role of Smug1 in the repair of lesions generated by oxidation of cytosine.
  The EMBO Journal 06/2005; 24(12):2205-13. · 9.20 Impact Factor
• Article: Mutation frequencies and AID activation state in B-cell lymphomas from Ung-deficient mice.

  Hilde Nilsen, Qian An, Tomas Lindahl
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  ABSTRACT: B-cell lymphomas arising in lymph nodes and spleen of aging mice deficient in the Ung DNA glycosylase were recovered, dispersed, grown in short-term culture, and CD19-positive B-cells retrieved and analysed. Several tumors as well as controls only expressed detectable amounts of the Aid deaminase after mitogenic stimulation, as estimated by real-time PCR of transcripts. However, one unusually large lymph node tumor expressed a high level of Aid constitutively. This particular tumor also showed a substantially increased mutation frequency in the Aid gene itself as well as in the bcl-6 and c-myc genes, but not in the p53 gene, consistent with aberrant somatic hypermutation. Other B-cell lymphomas from Ung(-/-) mice exhibited a modest increase in mutation frequency.
  Oncogene 05/2005; 24(18):3063-6. · 6.37 Impact Factor
• Article: Inroads into base excision repair I. The discovery of apurinic/apyrimidinic (AP) endonuclease. "An endonuclease for depurinated DNA in Escherichia coli B," Canadian Journal of Biochemistry, 1972.

  Tomas Lindahl, W G Verly, Paquette Y
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  ABSTRACT: DNA treated with alkylating agents is incised at sites of damage by cell extracts. A key component of this DNA repair function was shown by Verly and co-workers to be an endonuclease acting at secondary lesions, apurinic sites, rather than directly at alkylated nucleotide residues.
  DNA Repair 12/2004; 3(11):1522-30; discussion 1521. · 4.14 Impact Factor
• Article: Demethylation of 3-methylthymine in DNA by bacterial and human DNA dioxygenases.

  Pertti Koivisto, Peter Robins, Tomas Lindahl, Barbara Sedgwick
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  ABSTRACT: Rare DNA lesions that are chemically stable and refractory to repair may add disproportionately to the accumulation of mutations in long lived cells. 3-Methylthymine is a minor lesion that is induced by DNA-methylating agents and for which no repair process has been described previously. Here we demonstrate that this lesion can be directly demethylated in vitro by bacterial and human DNA dioxygenases. The Escherichia coli AlkB and human ABH3 proteins repaired 3-methylthymine in both single-stranded and double-stranded polydeoxynucleotides, whereas the human ABH2 protein preferred a duplex substrate. Thus, the known substrates of these enzymes now include 3-methylthymine in DNA, as well as 1-methyladenine and 3-methylcytosine, which all have structurally similar sites of alkylation. Repair of 3-methylthymine by AlkB and ABH3 was optimal at pH 6, but inefficient. At physiological pH, 3-methylthymine, which is a minor methylated lesion, was more slowly repaired than the major lesion generated in single-stranded DNA, 3-methylcytosine. Our data suggest that 3-methylthymine residues in DNA will be repaired inefficiently in vivo and therefore may occur at a low steady-state level, but the residues should not gradually accumulate to high levels in long lived cells.
  Journal of Biological Chemistry 10/2004; 279(39):40470-4. · 4.77 Impact Factor
• Article: Gene-targeted mice lacking the Trex1 (DNase III) 3'-->5' DNA exonuclease develop inflammatory myocarditis.

  Masashi Morita, Gordon Stamp, Peter Robins, Anna Dulic, Ian Rosewell, Geza Hrivnak, Graham Daly, Tomas Lindahl, Deborah E Barnes
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  ABSTRACT: TREX1, originally designated DNase III, was isolated as a major nuclear DNA-specific 3'-->5' exonuclease that is widely distributed in both proliferating and nonproliferating mammalian tissues. The cognate cDNA shows homology to the editing subunit of the Escherichia coli replicative DNA polymerase III holoenzyme and encodes an exonuclease which was able to serve a DNA-editing function in vitro, promoting rejoining of a 3' mismatched residue in a reconstituted DNA base excision repair system. Here we report the generation of gene-targeted Trex1(-/-) mice. The null mice are viable and do not show the increase in spontaneous mutation frequency or cancer incidence that would be predicted if Trex1 served an obligatory role of editing mismatched 3' termini generated during DNA repair or DNA replication in vivo. Unexpectedly, Trex1(-/-) mice exhibit a dramatically reduced survival and develop inflammatory myocarditis leading to progressive, often dilated, cardiomyopathy and circulatory failure.
  Molecular and Cellular Biology 08/2004; 24(15):6719-27. · 5.53 Impact Factor
• Source

  Available from: Eleonora Parlanti

  Article: Accumulation of the oxidative base lesion 8-hydroxyguanine in DNA of tumor-prone mice defective in both the Myh and Ogg1 DNA glycosylases.

  Maria Teresa Russo, Gabriele De Luca, Paolo Degan, Eleonora Parlanti, Eugenia Dogliotti, Deborah E Barnes, Tomas Lindahl, Hanjing Yang, Jeffrey H Miller, Margherita Bignami
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  ABSTRACT: The OGG1 and MYH DNA glycosylases prevent the accumulation of DNA 8-hydroxyguanine. In Myh(-/-) mice, there was no time-dependent accumulation of DNA 8-hydroxyguanine in brain, small intestine, lung, spleen, or kidney. Liver was an exception to this general pattern. Inactivation of both MYH and OGG1 caused an age-associated accumulation of DNA 8-hydroxyguanine in lung and small intestine. The effects of abrogated OGG1 and MYH on hepatic DNA 8-hydroxyguanine levels were additive. Because there is an increased incidence of lung and small intestine cancer in Myh(-/-)/Ogg1(-/-) mice, these findings support a causal role for unrepaired oxidized DNA bases in cancer development.
  Cancer Research 08/2004; 64(13):4411-4. · 7.86 Impact Factor
• Article: Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors.

  Yali Xie, Hanjing Yang, Cristina Cunanan, Kimberly Okamoto, Darryl Shibata, Janet Pan, Deborah E Barnes, Tomas Lindahl, Michael McIlhatton, Richard Fishel, Jeffrey H Miller
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  ABSTRACT: Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.
  Cancer Research 06/2004; 64(9):3096-102. · 7.86 Impact Factor