Arne Klungland*Yun-Gui Yang*b

1Department of Microbiology，Division of Diagnostics and Intervention，Institute of Clinical Medicine，Oslo University

Hospital，Rikshospitalet，Oslo NO-0027，Norway

2Department of Molecular Medicine，F(xiàn)aculty of Medicine，Institute of Basic Medical Sciences，University of Oslo，Oslo NO-0027，Norway

3CAS Key Laboratory of Genomic and Precision Medicine，Collaborative Innovation Center of Genetics and Development，Beijing Institute of Genomics，Chinese Academy of Sciences，Beijing 100101，China

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NEWS AND VIEWS

Endogenous DNA Damage and Repair Enzymes—A short summary of the scientific achievements of Tomas Lindahl，Nobel Laureate in Chemistry 2015

Arne Klungland1，2，*，a，Yun-Gui Yang3，*，b

1Department of Microbiology，Division of Diagnostics and Intervention，Institute of Clinical Medicine，Oslo University

Hospital，Rikshospitalet，Oslo NO-0027，Norway

2Department of Molecular Medicine，F(xiàn)aculty of Medicine，Institute of Basic Medical Sciences，University of Oslo，Oslo NO-0027，Norway

3CAS Key Laboratory of Genomic and Precision Medicine，Collaborative Innovation Center of Genetics and Development，Beijing Institute of Genomics，Chinese Academy of Sciences，Beijing 100101，China

Available online 12 December 2015

Handled by Zhao-Qi Wang

AbstractTomas Lindahl completed his medical studies at Karolinska Institute in 1970.Yet，his work has always been dedicated to unraveling fundamental mechanisms of DNA decay and DNA repair.His research is characterized with groundbreaking discoveries on the instability of our genome，the identification of novel DNA repair activities，the characterization of DNA repair pathways，and the association to diseases，throughout his 40 years of scientific career.

DNA is the genetic material that transmits all genetic information to the offspring and to do this faithfully，DNA was for long presumed to be absolutely stable.This hypothesis was challenged by the early study of Lindahl—Rate of depurination of native DNA［1］.He also identified numerous endogenous sources of DNA damage［2-4］.The number of DNA damages in a single human cell exceeds 10，000 every day and must be counteracted by special DNA repair processes.Tomas Lindahl summarized crucial knowledge on endogenous DNA damage and repair in an important review in 1993—Instability and decay of the primary structure of DNA［5］.This review also communicated fundamental knowledge on the stability of DNA to a broad audience.

Base excision repair is the repair pathway that handles most of the spontaneous lesions to our genome，such as abasic site（AP site），uracil，and various alkylated-or oxidized-DNA bases.Tomas Lindahl identified a New class of enzymes acting on damaged DNA，including uracil［6，7］，the DNA glycosylases.He further characterized DNA glycosylases specific for numerousdamagedbasesincludingmethylated［8］and oxidized bases［9］.Furthermore，he described in detail the single-nucleotide repair patches generated following repair of uracil［10］and went on to identify all enzymes required for complete base excision repair on naked DNA and on nucleosomes［11-14］.

An even more sophisticated strategy for DNA repair，the adaptive response to alkylating agents，was characterized in a series of ground-breaking studies.First，he identified the methylated guanine required for the adaptive response［15］and later identified the intracellular signal［16］and the ada gene product with two unique functions in the induction of alkylation resistance［17］.Tomas Lindahl’s group was also the key to the identification and characterization of the AlkB family of dioxygenases［18-20］.The AlkB repair mechanism was later shown to have fundamental importance for histone demethylation，5-methylChydroxylation，andreversible RNA methylation.

The list of enzymes，including various DNA glycosylases，alkyltransferases，endo-and exonucleases identified and characterized by Tomas Lindahl’s group for various aspects of DNA metabolisms is nearly endless.Some examples are early studies on uracil［21］，hypoxanthine［22］，processing of DNA 5′terminal ends［23］，poly（ADP-ribose）［24］，and the DNA ligases that complete various repair pathways by sealing nicks in DNA［26，27］，as well as more recent studies on Trex1-mediateddegradationofsingle-stranded（ssDNA）［25］.Several mammalian repair enzymes were further characterized by the design of gene-targeted mice［28-31］.

It is probably less known that Tomas Lindahl，early in his scientific life，also did ground-breaking studies on the genome of the Epstein-Barr virus（EBV）.Of major interest was his initial characterization of the circular EBV genome［32］.This study was followed up with a series of important publications of the EBV DNA in cancer cell lines（e.g.，［33］）and also includedtheidentificationofsequencevariantsofthe Epstein-Barr genome［34］.

Tomas Lindahl started his scientific career at Karolinska Institute，where he completed his PhD in 1967.He did his postdoctoral training at the Princeton University and the Rockefeller University and then became a professor at the University of Gothenburg in 1978.He is world-wide renowned also for directing the Clare Hall laboratories，part of Cancer Research UK that became a wonderful place to work and a leading center for studies on DNA repair and related processes.

On a more personal note；one，out of many，remarkable experiencesworkingaspostdocsinTomasLindahl’s group at Clare Hall，was his daily walks through his laboratory asking everybody‘‘how is it going”，which could lead to a shortansweroraone-hourscientificdiscussion.This guidance has continued for years after completing our postdoctoral training at Clare Hall，for which we are truly grateful.

Tomas Lindahl gave a keynote presentation at the‘‘Tomas Lindahl Conference on DNA Repair”（Figure 1），organized byhistwoformerpostdocsDrs.Yun-GuiYangand Arne Klungland in Oslo on June 20，2015（Figure 2）.

Figure 1　Keynote presentation by Tomas Lindahl at the‘‘Tomas Lindahl Conference on DNA Repair’’，Holmenkollen，Oslo，2015

References

［1］Lindahl T，Nyberg B.Rate of depurination of native deoxyribonucleic acid.Biochemistry 1972；11:3610-8.

［2］Karran P，Lindahl T.Hypoxanthine in deoxyribonucleic acid: generation by heat-induced hydrolysis of adenine residues and release in free form by a deoxyribonucleic acid glycosylase from calf thymus.Biochemistry 1980；19:6005-11.

［3］Rydberg B，Lindahl T.Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction.EMBO J 1982；1:211-6.

［4］Breimer LH，Lindahl T.Thymine lesions produced by ionizing radiationindouble-strandedDNA.Biochemistry1985；24: 4018-22.

［5］Lindahl T.Instability and decay of the primary structure of DNA. Nature 1993；362:709-15.

［6］Lindahl T.New class of enzymes acting on damaged DNA. Nature 1976；259:64-6.

［7］Lindahl T.An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci U S A 1974；71:3649-53.

［8］Chetsanga CJ，Lindahl T.Release of 7-methylguanine residues whose imidazole rings have been opened from damaged DNA by a DNA glycosylase from Escherichia coli.Nucleic Acids Res 1979；6:3673-84.

［9］Rolda′n-Arjona T，Wei YF，Carter KC，Klungland A，Anselmino C，Wang RP.Molecular cloning and functional expression of a human cDNA encoding the antimutator enzyme 8-hydroxyguanine-DNA glycosylase.Proc Natl Acad Sci U S A 1997；94:8016-20.

［10］Dianov G，Price A，Lindahl T.Generation of single-nucleotide repair patches following excision of uracil residues from DNA. Mol Cell Biol 1992；12:1605-12.

［11］Dianov G，Lindahl T.Reconstitution of the DNA base excisionrepair pathway.Curr Biol 1994；4:1069-76.

［12］Kubota Y，Nash RA，Klungland A，Schar P，Barnes DE，Lindahl T.Reconstitution of DNA base excision-repair with purified human proteins:interaction between DNA polymerase beta and the XRCC1 protein.EMBO J 1996；15:6662-70.

［13］Klungland A，Lindahl T.Second pathway for completion of human DNA base excision-repair:reconstitution with purified proteins and requirement for DNase IV（FEN1）.EMBO J 1997；16:3341-8.

［14］Nilsen H，Haushalter KA，Robins P，Barnes DE，Verdine GL，Lindahl T.Excision of deaminated cytosine from the vertebrate genome:role of the SMUG1 uracil-DNA glycosylase.EMBO J 2001；20:4278-86.

［15］Karran P，Lindahl T，Griffin B.Adaptive response to alkylating agents involves alteration in situ of O6-methylguanine residues in DNA.Nature 1979；280:76-7.

［16］Teo I，Sedgwick B，Kilpatrick MW，McCarthy TV，Lindahl T. The intracellular signal for induction of resistance to alkylating agents in E.coli.Cell 1986；45:315-24.

［17］Teo I，Sedgwick B，Demple B，Li B，Lindahl T.Induction of resistance to alkylating agents in E.coli:the ada+gene product serves both as a regulatory protein and as an enzyme for repair of mutagenic damage.EMBO J 1984；3:2151-7.

［18］Trewick SC，Henshaw TF，Hausinger RP，Lindahl T，Sedgwick B. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.Nature 2002；419:174-8.

［19］Duncan T，Trewick SC，Koivisto P，Bates PA，Lindahl T，Sedgwick B.Reversal of DNA alkylation damage by two human dioxygenases.Proc Natl Acad Sci U S A 2002；99: 16660-5.

［20］Dinglay S，Trewick SC，Lindahl T，Sedgwick B.Defective processing of methylated single-stranded DNA by E.coli AlkB mutants.Genes Dev 2000；14:2097-105.

［21］Lindahl T，Ljungquist S，Siegert W，Nyberg B，Sperens B.DNA N-glycosidases:propertiesofuracil-DNAglycosidasefrom Escherichia coli.J Biol Chem 1977；252:3286-94.

［22］Karran P，Lindahl T.Enzymatic excision of free hypoxanthine from polydeoxynucleotides and DNA containing deoxyinosine monophosphate residues.J Biol Chem 1978；253:5877-9.

［23］Lindahl T，Gally JA，Edelman GM.Deoxyribonuclease IV:a new exonuclease from mammalian tissues.Proc Natl Acad Sci U S A 1969；62:597-603.

［24］Satoh MS，Lindahl T.Role of poly（ADP-ribose）formation in DNA repair.Nature 1992；356:356-8.

［25］Yang YG，Lindahl T，Barnes DE.Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.Cell 2007；131:873-86.

［26］Barnes DE，Johnston LH，Kodama K，Tomkinson AE，Lasko DD，Lindahl T.Human DNA ligase I cDNA:cloning and functional expression in Saccharomyces cerevisiae.Proc Natl Acad Sci U S A 1990；87:6679-83.

Figure 2　Yun-Gui Yang（left）and Arne Klungland（right）with Tomas Lindahl at the‘‘Tomas Lindahl Conference on DNA Repair’’，Holmenkollen，Oslo，2015

［27］Tomkinson AE，Roberts E，Daly G，Totty NF，Lindahl T.Three distinctDNAligasesinmammaliancells.JBiolChem 1991；266:21728-35.

［28］Barnes DE，Stamp G，Rosewell I，Denzel A，Lindahl T.Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice.Curr Biol 1998；8:1395-8.

［29］Nilsen H，Rosewell I，Robins P，Skjelbred CF，Andersen S，Slupphaug G.Uracil-DNA glycosylase（UNG）-deficient mice reveal a primary role of the enzyme during DNA replication.Mol Cell 2000；5:1059-65.

［30］Morita M，Stamp G，Robins P，Dulic A，Rosewell I，Hrivnak G. Gene-targeted mice lacking the Trex1（DNase III）3′→5′DNA exonuclease develop inflammatory myocarditis.Mol Cell Biol 2004；24:6719-27.

［31］Klungland A，Rosewell I，Hollenbach S，Larsen E，Daly G，Epe B，et al.Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage.Proc Natl Acad Sci U S A 1999；96:13300-5.

［32］Adams A，Lindahl T.Epstein-Barr virus genomes with properties of circular DNA molecules in carrier cells.Proc Natl Acad Sci U S A 1975；72:1477-81.

［33］Kaschka-Dierich C，Adams A，Lindahl T，Bornkamm GW，BjursellG，KleinG.IntracellularformsofEpstein-Barr virus DNA in human tumour cells in vivo.Nature 1976；260: 302-6.

［34］Rymo L，Lindahl T，Adams A.Sites of sequence variability in Epstein-Barr virus DNA from different sources.Proc Natl Acad Sci U S A 1979；76:2794-8.

23 October 2015；accepted 12 November 2015

*Corresponding authors.

E-mail:arne.klungland@medisin.uio.no（Klungland A），ygyang@ big.ac.cn（Yang YG）.

aORCID:0000-0001-7274-3661.

bORCID:0000-0002-2821-8541.

Peer review under responsibility of Beijing Institute of Genomics，Chinese Academy of Sciences and Genetics Society of China.

http://dx.doi.org/10.1016/j.gpb.2015.11.001

1672-0229?2015 The Authors.Production and hosting by Elsevier B.V.on behalf of Beijing Institute of Genomics，Chinese Academy of Sciences and Genetics Society of China.

This is an open access article under the CC BY license（http://creativecommons.org/licenses/by/4.0/）.