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Science 291 (5507): 1284-1289

Copyright © 2001 by the American Association for the Advancement of Science

Human DNA Repair Genes

Richard D. Wood,1* Michael Mitchell,2 John Sgouros,2 Tomas Lindahl1

Cellular DNA is subjected to continual attack, both by reactive species inside cells and by environmental agents. Toxic and mutagenic consequences are minimized by distinct pathways of repair, and 130 known human DNA repair genes are described here. Notable features presently include four enzymes that can remove uracil from DNA, seven recombination genes related to RAD51, and many recently discovered DNA polymerases that bypass damage, but only one system to remove the main DNA lesions induced by ultraviolet light. More human DNA repair genes will be found by comparison with model organisms and as common folds in three-dimensional protein structures are determined. Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process.

1 Imperial Cancer Research Fund, Clare Hall Laboratories, Blanche Lane, South Mimms, Herts EN6 3LD, UK.
2 Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
*   Present address: University of Pittsburgh Cancer Institute, S867 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.


The human genome, like other genomes, encodes information to protect its own integrity (1). DNA repair enzymes continuously monitor chromosomes to correct damaged nucleotide residues generated by exposure to carcinogens and cytotoxic compounds. The damage is partly a consequence of environmental agents such as ultraviolet (UV) light from the sun, inhaled cigarette smoke, or incompletely defined dietary factors. However, a large proportion of DNA alterations are caused unavoidably by endogenous weak mutagens including water, reactive oxygen species, and metabolites that can act as alkylating agents. Very slow turnover of DNA consequently occurs even in cells that do not proliferate. Genome instability caused by the great variety of DNA-damaging agents would be an overwhelming problem for cells and organisms if it were not for DNA repair.

On the basis of searches of the current draft of the human genome sequence (2), we compiled a comprehensive list of DNA repair genes (Table 1). This inventory focuses on genes whose products have been functionally linked to the recognition and repair of damaged DNA as well as those showing strong sequence homology to repair genes in other organisms. Readers desiring further information on specific genes should consult the primary references and links available through the accession numbers. Recent review articles on the evolutionary relationships of DNA repair genes (3) and common sequence motifs in DNA repair genes (4) may also be helpful.

Table 1. Human DNA repair genes. A version of this table with active links to Gene Cards (bioinformatics.weizmann.ac.il/cards) and to the National Center for Biotechnology Information is available (24) on Science Online. A version with updates is available at www.cgal.icnet.uk/DNA_Repair_Genes.html. XP, xeroderma pigmentosum.


Gene name (synonyms) Activity Chromosome location Accession number

Base excision repair (BER)
DNA glycosylases: major altered base released
UNG U 12q23-q24.1 NM_003362
SMUG1 U 12q13.1-q14 NM_014311
MBD4 U or T opposite G at CpG sequences 3q21-q22 NM_003925
TDG U, T or ethenoC opposite G 12q24.1 NM_003211
OGG1 8-oxoG opposite C 3p26.2 NM_002542
MYH A opposite 8-oxoG 1p34.3-p32.1 NM_012222
NTH1 Ring-saturated or fragmented pyrimidines 16p13.3-p13.2 NM_002528
MPG 3-meA, ethenoA, hypoxanthine 16p13.3 NM_002434
Other BER factors
APE1 (HAP1, APEX, REF1) AP endonuclease 14q12 NM_001641
APE2 (APEXL2) AP endonuclease X NM_014481
LIG3 Main ligation function 17q11.2-q12 NM_013975
XRCC1 Main ligation function 19q13.2 NM_006297
Poly(ADP-ribose) polymerase (PARP) enzymes
ADPRT Protects strand interruptions 1q42 NM_001618
ADPRTL2 PARP-like enzyme 14q11.2-q12 NM_005485
ADPRTL3 PARP-like enzyme 3p21.1-p22.2 AF085734
Direct reversal of damage
MGMT O6-meG alkyltransferase 10q26 NM_002412
Mismatch excision repair (MMR)
MSH2 Mismatch and loop recognition 2p22-p21 NM_000251
MSH3 Mismatch and loop recognition 5q11-q12 NM_002439
MSH6 Mismatch recognition 2p16 NM_000179
MSH4 MutS homolog specialized for meiosis 1p31 NM_002440
MSH5 MutS homolog specialized for meiosis 6p21.3 NM_002441
PMS1 Mitochondrial MutL homolog 2q31.1 NM_000534
MLH1 MutL homolog 3p21.3 NM_000249
PMS2 MutL homolog 7p22 NM_000535
MLH3 MutL homolog of unknown function 14q24.3 NM_014381
PMS2L3 MutL homolog of unknown function 7q11-q22 D38437
PMS2L4 MutL homolog of unknown function 7q11-q22 D38438
Nucleotide excision repair (NER)
XPC Binds damaged DNA as complex 3p25 NM_004628
RAD23B (HR23B) Binds damaged DNA as complex 3p25.1 NM_002874
CETN2 Binds damaged DNA as complex Xq28 NM_004344
RAD23A (HR23A) Substitutes for HR23B 19p13.2 NM_005053
XPA Binds damaged DNA in preincision complex 9q22.3 NM_000380
RPA1 Binds DNA in preincision complex 17p13.3 NM_ 002945
RPA2 Binds DNA in preincision complex 1p35 NM_002946
RPA3 Binds DNA in preincision complex 7p22 NM_002947
TFIIH Catalyzes unwinding in preincision complex
XPB (ERCC3) 3' to 5' DNA helicase 2q21 NM_000122
XPD (ERCC2) 5' to 3' DNA helicase 19q13.2-q13.3 X52221
GTF2H1 Core TFIIH subunit p62 11p15.1-p14 NM_005316
GTF2H2 Core TFIIH subunit p44 5q12.2-q13.3 NM_001515
GTF2H3 Core TFIIH subunit p34 12q NM_001516
GTF2H4 Core TFIIH subunit p52 6p21.3 NM_001517
CDK7 Kinase subunit of TFIIH 2p15-cen NM_001799
CCNH Kinase subunit of TFIIH 5q13.3-q14 NM_001239
MNAT1 Kinase subunit of TFIIH 14q23 NM_002431
XPG (ERCC5) 3' incision 13q33 NM_000123
ERCC1 5' incision subunit 19q13.2-q13.3 NM_001983
XPF (ERCC4) 5' incision subunit 16p13.3-p13.13 NM_005236
LIG1 DNA joining 19q13.2-q13.3 NM_000234
NER-related
CSA (CKN1) Cockayne syndrome; needed for transcription-coupled NER 5q12-q31 NM_000082
CSB (ERCC6) Cockayne syndrome; needed for transcription-coupled NER 10q11 NM_000124
XAB2 (HCNP) Cockayne syndrome; needed for transcription-coupled NER 19 NM_020196
DDB1 Complex defective in XP group E 11q12-q13 NM_001923
DDB2 Mutated in XP group E 11p12-p11 NM_000107
MMS19 Transcription and NER 10q24.1 AW852889
Homologous recombination
RAD51 Homologous pairing 15q15.1 NM_002875
RAD51L1 (RAD51B) Rad51 homolog 14q23-q24 U84138
RAD51C Rad51 homolog 17q11-qter NM_002876
RAD51L3 (RAD51D) Rad51 homolog 17q11 NM_002878
Gene name (synonyms) Activity Chromosome location Accession number

DMC1 Rad51 homolog, meiosis 22q13.1 NM_007068
XRCC2 DNA break and cross-link repair 7q36.1 NM_005431
XRCC3 DNA break and cross-link repair 14q32.3 NM_005432
RAD52 Accessory factor for recombination 12p13-p12.2 NM_002879
RAD54L Accessory factor for recombination 1p32 NM_003579
RAD54B Accessory factor for recombination 8q21.3-q22 NM_012415
BRCA1 Accessory factor for transcription and recombination 17q21 NM_007295
BRCA2 Cooperation with RAD51, essential function 13q12.3 NM_000059
RAD50 ATPase in complex with MRE11A, NBS1 5q31 NM_005732
MRE11A 3' exonuclease 11q21 NM_005590
NBS1 Mutated in Nijmegen breakage syndrome 8q21-q24 NM_002485
mdit>Nonhomologous end-joining
Ku70 (G22P1) DNA end binding 22q13.2-q13.31 NM_001469
Ku80 (XRCC5) DNA end binding 2q35 M30938
PRKDC DNA-dependent protein kinase catalytic subunit 8q11 NM_006904
LIG4 Nonhomologous end-joining 13q33-q34 NM_002312
XRCC4 Nonhomologous end-joining 5q13-q14 NM_003401
Sanitization of nucleotide pools
MTH1 (NUDT1) 8-oxoGTPase 7p22 NM_002452
DUT dUTPase 15q15-q21.1 NM_001948
DNA polymerases (catalytic subunits)
POLB BER in nuclear DNA 8p11.2 NM_002690
POLG BER in mitochondrial DNA 15q25 NM_002693
POLD1 NER and MMR 19q13.3 NM_002691
POLE1 NER and MMR 12q24.3 NM_006231
PCNA Sliding clamp for pol delta and pol epsilon 20p12 NM_002592
REV3L (POLZ) DNA pol zeta catalytic subunit, essential function 6q21 NM_002912
REV7 (MAD2L2) DNA pol zeta subunit 1p36 NM_006341
REV1 dCMP transferase 2q11.1-q11.2 NM_016316
POLH XP variant 6p12.2-p21.1 NM_006502
POLI (RAD30B) Lesion bypass 18q21.1 NM_007195
POLQ DNA cross-link repair 3q13.31 NM_006596
DINB1 (POLK) Lesion bypass 5q13 NM_016218
POLL Meiotic function 10q23 NM_013274
POLM Presumed specialized lymphoid function 7p13 NM_013284
TRF4-1 Sister-chromatid cohesion 5p15 AF089896
TRF4-2 Sister-chromatid cohesion 16p13.3 AF089897
Editing and processing nucleases
FEN1 (DNase IV) 5' nuclease 11q12 NM_004111
TREX1 (DNase III) 3' exonuclease 3p21.2-p21.3 NM_007248
TREX2 3' exonuclease Xq28 NM_007205
EX01 (HEX1) 5' exonuclease 1q42-q43 NM_003686
SPO11 endonuclease 20q13.2-q13.3 NM_012444
Rad6 pathway
UBE2A (RAD6A) Ubiquitin-conjugating enzyme Xq24-q25 NM_003336
UBE2B (RAD6B) Ubiquitin-conjugating enzyme 5q23-q31 NM_003337
RAD18 Assists repair or replication of damaged DNA 3p24-p25 AB035274
UBE2VE (MMS2) Ubiquitin-conjugating complex 8p AF049140
UBE2N (UBC13, BTG1) Ubiquitin-conjugating complex 12 NM_003348
Genes defective in diseases associated with sensitivity to DNA damaging agents
BLM Bloom syndrome helicase 15q26.1 NM_000057
WRN Werner syndrome helicase/3'-exonuclease 8p12-p11.2 NM_000553
RECQL4 Rothmund-Thompson syndrome 8q24.3 NM_004260
ATM Ataxia telangiectasia 11q22-q23 NM_000051
Fanconi anemia
FANCA Involved in tolerance or repair of DNA cross-links 16q24.3 NM_000135
FANCB Involved in tolerance or repair of DNA cross-links N/A N/A
FANCC Involved in tolerance or repair of DNA cross-links 9q22.3 NM_000136
FANCD Involved in tolerance or repair of DNA cross-links 3p26-p22 N/A
FANCE Involved in tolerance or repair of DNA cross-links 6p21-p22 NM_021922
FANCF Involved in tolerance or repair of DNA cross-links 11p15 AF181994
FANCG (XRCC9) Involved in tolerance or repair of DNA cross-links 9p13 NM_004629
Other identified genes with a suspected DNA repair function
SNM1 (PS02) DNA cross-link repair 10q25 D42045
SNM1B Related to SNM1 1p13.1-p13.3 AL137856
SNM1C Related to SNM1 10 AA315885
RPA4 Similar to RPA2 Xq NM_013347
ABH (ALKB) Resistance to alkylation damage 14q24 X91992
PNKP Converts some DNA breaks to ligatable ends 19q13.3-q13.4 NM_007254
Gene name (synonyms) Activity Chromosome location Accession number

Other conserved DNA damage response genes
ATR ATM- and PI-3K-like essential kinase 3q22-q24 NM_001184
RAD1 (S. pombe) homolog PCNA-like DNA damage sensor 5p13.3-p13.2 NM_002853
RAD9 (S. pombe) homolog PCNA-like DNA damage sensor 11q13.1-q13.2 NM_004584
HUS1 (S. pombe) homolog PCNA-like DNA damage sensor 7p13-p12 NM_004507
RAD17 (RAD24) RFC-like DNA damage sensor 5q13 NM_002873
TP53BP1 BRCT protein 15q15-q21 NM_005657
CHEK1 Effector kinase 11q22-q23 NM_001274
CHK2 (Rad53) Effector kinase 22q12.1 NM_007194

The functions required for the three distinct forms of excision repair are described separately. These are base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Additional sections discuss direct reversal of DNA damage, recombination and rejoining pathways for repair of DNA strand breaks, and DNA polymerases that can bypass DNA damage.

The BER proteins excise and replace damaged DNA bases, mainly those arising from endogenous oxidative and hydrolytic decay of DNA (1). DNA glycosylases initiate this process by releasing the modified base. This is followed by cleavage of the sugar-phosphate chain, excision of the abasic residue, and local DNA synthesis and ligation. Cell nuclei and mitochondria contain several related but nonidentical DNA glycosylases obtained through alternative splicing of transcripts. Three different nuclear DNA glycosylases counteract oxidative damage, and a fourth mainly excises alkylated purines. Remarkably, four of the eight identified DNA glycosylases can remove uracil from DNA. Each of them has a specialized function, however. UNG, which is homologous to the Escherichia coli Ung enzyme, is associated with DNA replication forks and corrects uracil misincorporated opposite adenine. SMUG1, which is unique to higher eukaryotes, probably removes the uracil that arises in DNA by deamination of cytosine. MBD4 excises uracil and thymine specifically at deaminated CpG and 5-methyl-CpG sequences, and TDG removes ethenoC, a product of lipid peroxidation, and also slowly removes uracil and thymine at G·U and G·T base pairs. The existence of multiple proteins with similar activities is a recurring theme in human DNA repair (1). Another illustration of this is the set of at least four adenosine triphosphate (ATP)-dependent DNA ligases encoded by three genes, with LIG3-XRCC1 providing the main nick-joining function for BER.

Until recently, only one endonuclease for abasic sites had been found encoded in the human genome, although there are two each in E. coli and the yeast Saccharomyces cerevisiae and three genes are predicted in the genome of the plant Arabidopsis thaliana. A second human gene, APE2, has recently appeared. Apparently this encodes a minor activity, as deletion of the major gene APE1 causes early embryonic lethality in mice. Repair of the DNA replication-blocking lesion 3-methyladenine is another case where the human genome is frugal. In other organisms, several DNA glycosylases, unrelated at the primary sequence level, can remove 3-meA. Among them are Tag1 of E. coli, AlkA of E. coli (similar to MAG of S. cerevisiae), and MPG in higher eukaryotes. Only the MPG enzyme has been characterized so far in the human genome. This is in contrast to the at least two alkA and six tag1 homologs found in Arabidopsis (5). However, like the genomes of other multicellular animals, the current human genome draft contains no obvious tag1 and alkA homologs (6).

A few unusual enzymes reverse rather than excise DNA damage. The human MGMT removes methyl groups and other small alkyl groups from the O6 position of guanine. There are two such proteins (Ada and Ogt) in E. coli, but no additional homologs have been detected in the human genome sequence. MGMT resembles the COOH-terminal half of Ada. The NH2-terminal half of E. coli Ada can remove a methyl group from a DNA phosphate residue. We found no homologs of this region of Ada, and it remains unclear whether such backbone methylations are repaired in human cells.

Many organisms contain photolyases that can monomerize lesions induced by UV light such as cyclobutane pyrimidine dimers and (6-4) photoproducts. The human genome has two CRY genes with similarity to photolyase sequences. These encode blue light photoreceptors involved in setting of circadian rhythms but not in photoreactivation of DNA damage. We have not detected additional homologs of DNA repair photolyases in the human genome, confirming previous reports that photolyase activity is present in many vertebrates including fish, reptiles, and marsupials, but not in placental mammals.

NER mainly removes bulky adducts caused by environmental agents. In E. coli, the three polypeptides UvrA, UvrB, and UvrC can locate a lesion and incise on either side of it to remove a segment of nucleotides containing the damage. Eukaryotes, including yeast and human cells, do not have direct UvrABC homologs but use a more elaborate assembly of gene products to carry out NER (1). For example, E. coli UvrA can bind to sites of DNA damage, whereas at least four different human NER factors have this property (the XPC complex, DDB complex, XPA, and RPA). The formation of an unwound preincision intermediate in human cells requires two DNA helicases, XPB and XPD, instead of the single UvrB in E. coli, and there are dedicated human nucleases (XPG and ERCC1-XPF) for each of the two incisions, instead of the single UvrC in bacteria. S. cerevisiae encodes two additional gene products, Rad7 and Rad16, which are important for NER. No convincing homologs to these can be identified in the human genome, although Rad16 is a difficult case because it is a member of the amply represented Swi/Snf family of DNA-stimulated adenosine triphosphatases (ATPases).

Some organisms such as the fission yeast Schizosaccharomyces pombe have a second system for excision of pyrimidine dimers, initiated by a UVDE nuclease. The human genome apparently lacks a homolog of this nuclease and has no such backup system, consistent with the fact that cells from NER-defective xeroderma pigmentosum patients totally lack the ability to remove pyrimidine dimers from DNA.

The transcribed strand of active human genes is repaired faster than the nontranscribed strand in a transcription-coupled repair process known to involve the products of CSA, CSB, and XAB2. The mechanism of such transcription-coupled repair is not known, and future investigation is expected to reveal additional participants.

MMR corrects occasional errors of DNA replication as well as heterologies formed during recombination. The bacterial mutS and mutL genes encode proteins responsible for identifying mismatches, and there are numerous homologs of these genes in the human genome, of greater variety than those found in yeast, Drosophila melanogaster, or Caenorhabditis elegans. Some of these proteins are specialized for locating distinct types of mismatches in DNA, some are specialized for meiotic recombination, and some have functions yet to be determined. In E. coli, the newly synthesized DNA strand is identified with the aid of the MutH endonuclease, which has no human ortholog. Strand discrimination in human cells may be signaled instead by the orientation of components of the DNA replication complex such as PCNA or by other factors not yet identified.

DNA double-strand breaks may be rectified by either homologous or nonhomologous recombination pathways. Particularly notable in the human sequence is the presence of at least seven genes encoding proteins distantly related to the single Rad51 of S. cerevisiae and the single RecA of E. coli. The latter proteins function in strand pairing and exchange during recombination. By comparison, four members of the Rad51 family have been found in the Drosophila genome (7) and four in Arabidopsis (5). Homologous recombination in human cells is likely to involve branch migration enzymes and resolvases that are functionally analogous to the bacterial RuvABC system. Recent biochemical experiments have revealed human activities for such concerted branch migration/resolution reactions, but the responsible gene products have not yet been identified (8).

The nonhomologous end-joining pathway (NHEJ) involves the factors listed in Table 1, and additional components will most likely be discovered. For example, the DNA-dependent protein kinase is believed to phosphorylate key molecules involved in the repair process. These substrates have yet to be fully defined.

Single-strand interruptions in DNA can be rectified by enzymes from the BER pathway. Enzymes of the PARP family, as well as XRCC1, temporarily bind to single-strand interruptions in DNA and may act to recruit repair proteins. We have not listed the telomere-binding proteins protecting the ends of chromosomes, but one member of the PARP family, tankyrase, is present in this complex.

During the past year, the human genome sequence has revealed many previously unrecognized DNA polymerases (1). There are currently at least 15 DNA polymerases in humans, exceeding the number found in any other organism. For repair of nuclear DNA, the main form of BER uses Pol beta , whereas Pol delta  or Pol epsilon  are the main enzymes employed for NER and MMR. Genetic and biochemical evidence has implicated many of the newly discovered polymerases in the DNA damage response, but others may have specialized roles such as sister chromatid cohesion. Table 1 includes the catalytic subunits of these DNA polymerases, but not other subunits and DNA polymerase cofactors.

REV3L, the catalytic subunit of DNA polymerase zeta , illustrates how DNA sequence homology searches can yield unexpected results. The DNA polymerase domain at the COOH-terminus of the human protein resembles S. cerevisiae Rev3, but most of the first 2000 amino acids are not present in the yeast protein. A second human gene highly homologous to 1200 residues in this region (outside the polymerase domains) is encoded on the X chromosome (accession number AL139395). It is premature to classify this as a DNA repair gene, but study of it is expected to shed light on the function of REV3L.

The human genome sequence has already markedly influenced the field of DNA repair. Many of the genes listed were discovered as investigators searched the expanding database for sequence similarity to genes discovered in model organisms. This approach will no doubt continue, and new human genes will be identified as additional repair functions are identified in other systems. One source that is likely to be fruitful is the genome of Deinococcus radiodurans (9). This bacterium has an exceptionally high resistance to DNA-damaging agents, especially ionizing radiation, in comparison to other microorganisms. Some of the currently uncharacterized genes in D. radiodurans are expected to contribute to DNA repair, and it remains to be seen if there will be homologs of such functions in the human genome.

The sequence database also makes it increasingly straightforward to use mass spectrometry fingerprinting to identify new subunits of repair protein complexes (10). In this sensitive technique, isolated proteins are digested with an enzyme such as trypsin, and the exact molecular masses of the resulting fragments are measured. Comparison of these fragments with a computer-simulated tryptic digest of each human gene product can unambiguously identify the protein.

In addition, new genes will be found as novel biochemical assays are developed for various aspects of repair. For example, human cells can repair cross-links between the two DNA strands. Interstrand cross-links are generated by natural psoralen compounds and their chemotherapeutic derivatives, by other drugs used for cancer treatment such as nitrogen mustards, and to some extent by ionizing and ultraviolet radiation. Repair of such cross-links involves the NER genes and the XRCC2 and XRCC3 recombination genes and is predicted to involve the DNA polymerase POLQ. In addition, the sensitivity of cells from individuals with Fanconi anemia (FA) points to a role for the FANC group of genes in cross-link repair. However, the mechanism of interstrand DNA cross-link repair remains obscure, and further investigation may implicate even more gene products.

Several other classes of DNA damage exist for which repair has been relatively unexplored. New genes may be identified, for instance, involved in the repair of damage caused by lipid peroxidation (1). Other uncharacterized forms of DNA damage caused by reactive metabolites and catabolites may be found. For example, the genome is dynamic, and single-stranded regions are temporarily exposed during DNA replication and gene transcription. Positions that are normally protected by base-pairing within the double helical structure are then vulnerable to group-specific reagents, creating new classes of lesions. Alkylating agents can form the cytotoxic lesions 1-methyladenine and 3-methylcytosine in single-stranded DNA, and new repair strategies may be needed to remove such lesions.

DNA is assembled into several levels of ordered chromatin structure, and so DNA metabolic processes need a close connection with proteins that allow chromatin remodeling or disassembly. Several human chromatin remodeling complexes are known, for instance, that allow and control access to DNA during gene transcription (11). The great majority of enzymological DNA repair studies to date have worked with naked DNA, but chromatin presents a substantial barrier to recognition of DNA damage. It is expected that human protein complexes will be found that are dedicated to DNA repair and recombination, facilitating access of DNA repair enzymes to the genome.

The three-dimensional structures of DNA repair proteins are being determined at an ever-increasing pace (12). Structural biologists will soon turn their attention to open reading frames of unknown function, and new repair genes will become apparent in the process. As an example, the functionally related SMUG1, TDG, and UNG enzymes show little or no primary sequence homology yet have common structural folds and belong to a single protein superfamily (13). As the structures of new protein folds are documented, more members of DNA repair enzyme families are likely to be found with the aid of three-dimensional structure prediction models. In this way, the new field of structural genomics will help guide functional studies of presently uncharacterized open reading frames in the human genome.

For an impressive number of genes involved in human DNA repair, disruptions of the corresponding murine genes have been reported (14), are in progress, or have recently been constructed. The results are beginning to guide searches for additional DNA repair enzymes. Knockouts of DNA glycosylases in mice have unexpectedly mild consequences by comparison with budding yeast and E. coli models. This implies that more backup systems exist, probably because endogenous damage presents a more frequent problem for larger genomes.

As the genes from the human genome sequence continue to be cataloged, studying the activity of the protein products will become increasingly important. More effective methods for rapid expression of active proteins will be required to test for possible functions. An alternative approach is to selectively inactivate individual proteins in vivo. An efficient method for selective proteolytic destruction has been successful in budding yeast (15) and should be extendable to mammalian cells. Alternatively, systematic interference with gene expression with the use of inhibitory RNA molecules, as employed successfully in C. elegans (16), is proving to be a powerful way to dissect gene functions.

Intense activity is being devoted to understanding how DNA damage transmits signals to the cell-cycle checkpoint machinery and to the monitoring systems that control cellular apoptosis. There is recent progress on this complex extended network, which involves damage recognition factors, protein kinases, and transcription factors such as p53 (17). Attempts are already being made to obtain an integrated picture of DNA repair with regard to signaling (18). The subject is of great interest as some inherited human syndromes associated with sensitivity to DNA-damaging agents result from loss of functions such as ATM, which is involved in damage sensing.

New clinical applications relating to human DNA repair genes are certain to emerge. Tumor cells often acquire resistance to therapeutic drugs or radiation. Genomics approaches such as array technology will be used to define any DNA repair genes that may be overexpressed in this context. Furthermore, it will be important to find ways to specifically inhibit DNA repair in these resistant cells by targeting the key enzymes. Genetic polymorphisms in relevant repair genes will be identified and efforts made to correlate them with effects on activity of the respective proteins, with response to particular therapies and with clinical outcomes. Although a number of polymorphisms in DNA repair genes are being reported, there is presently little functional information on the consequences of the attendant amino acid changes. It will be important to find out which polymorphisms actually affect protein function and then concentrate on these in epidemiological and clinical studies. For example, homozygosity for a particular polymorphism in the DNA ligase subunit XRCC1 is associated with higher sister chromatid exchange frequencies in smokers, suggesting an association of this allele with a higher risk for tobacco- and age-related DNA damage (19). Larger studies and comparison with other polymorphisms having known biochemical effects will be needed to further validate and extend these findings.

Furthermore, with the use of gene and protein array techniques, it should be possible to compare expression profiles of DNA repair genes in normal and tumor cells--information that could eventually lead to individually tailored therapies with chemicals and radiation. For example, tumors with low levels of NER should be more susceptible to treatment with cisplatin (20). In experimental systems, MMR-deficient cells are highly tolerant to alkylating chemotherapeutic drugs. MMR-defective tumors such as those found in hereditary nonpolyposis colon cancer may be resistant to treatment with such agents (21).

Some variation in DNA repair gene expression is epigenetic in origin and has been found for instance with MGMT and MSH6 (22). The MGMT gene promoter is often methylated in gliomas, resulting in suppressed expression that can be associated with an improved response after tumor treatment with an alkylating agent (23). The complete human genome sequence now allows the definition of promoter regions so that the DNA methylation status of relevant CpG islands can be investigated readily. Finally, DNA repair, especially repair of oxidative damage, has often been suggested as a relevant factor in counteracting aging. An examination of polymorphisms and gene expression levels in human DNA repair genes and a comparison with the equivalent genes in shorter lived mammalian species should help determine the importance of DNA repair in normal aging processes.

REFERENCES AND NOTES

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Polymorphisms in DNA Base Excision Repair Genes ADPRT and XRCC1 and Risk of Lung Cancer.
X. Zhang, X. Miao, G. Liang, B. Hao, Y. Wang, W. Tan, Y. Li, Y. Guo, F. He, Q. Wei, et al. (2005)
Cancer Res. 65, 722-726
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Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer.
O. Popanda, T. Schattenberg, C. T. Phong, D. Butkiewicz, A. Risch, L. Edler, K. Kayser, H. Dienemann, V. Schulz, P. Drings, et al. (2004)
Carcinogenesis 25, 2433-2441
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UV Light-induced DNA Damage and Tolerance for the Survival of Nucleotide Excision Repair-deficient Human Cells.
S. Nakajima, L. Lan, S.-i. Kanno, M. Takao, K. Yamamoto, A. P. M. Eker, and A. Yasui (2004)
J. Biol. Chem. 279, 46674-46677
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Irofulven Cytotoxicity Depends on Transcription-Coupled Nucleotide Excision Repair and Is Correlated with XPG Expression in Solid Tumor Cells.
F. Koeppel, V. Poindessous, V. Lazar, E. Raymond, A. Sarasin, and A. K. Larsen (2004)
Clin. Cancer Res. 10, 5604-5613
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Gene Expression Analysis of Tumor Spheroids Reveals a Role for Suppressed DNA Mismatch Repair in Multicellular Resistance to Alkylating Agents.
G. Francia, S. Man, B. Teicher, L. Grasso, and R. S. Kerbel (2004)
Mol. Cell. Biol. 24, 6837-6849
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Human Nucleotide Excision Repair Efficiently Removes Chromium-DNA Phosphate Adducts and Protects Cells against Chromate Toxicity.
M. Reynolds, E. Peterson, G. Quievryn, and A. Zhitkovich (2004)
J. Biol. Chem. 279, 30419-30424
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Identification of Genetic Variants in Base Excision Repair Pathway and Their Associations with Risk of Esophageal Squamous Cell Carcinoma.
B. Hao, H. Wang, K. Zhou, Y. Li, X. Chen, G. Zhou, Y. Zhu, X. Miao, W. Tan, Q. Wei, et al. (2004)
Cancer Res. 64, 4378-4384
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Involvement of base excision repair in response to therapy targeted at thymidylate synthase.
L. Li, S. H. Berger, and M. D. Wyatt (2004)
Mol. Cancer Ther. 3, 747-753
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High Specificity of Quantitative Excision Repair Cross-Complementing 1 Messenger RNA Expression for Prediction of Minor Histopathological Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer.
U. Warnecke-Eberz, R. Metzger, F. Miyazono, S. E. Baldus, S. Neiss, J. Brabender, H. Schaefer, W. Doerfler, E. Bollschweiler, H. P. Dienes, et al. (2004)
Clin. Cancer Res. 10, 3794-3799
   Abstract »    Full Text »    PDF »
DNA repair in higher plants; photoreactivation is the major DNA repair pathway in non-proliferating cells while excision repair (nucleotide excision repair and base excision repair) is active in proliferating cells.
S. Kimura, Y. Tahira, T. Ishibashi, Y. Mori, T. Mori, J. Hashimoto, and K. Sakaguchi (2004)
Nucleic Acids Res. 32, 2760-2767
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A Large-Scale Screen for Mutagen-Sensitive Loci in Drosophila.
A. Laurencon, C. M. Orme, H. K. Peters, C. L. Boulton, E. K. Vladar, S. A. Langley, E. P. Bakis, D. T. Harris, N. J. Harris, S. M. Wayson, et al. (2004)
Genetics 167, 217-231
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Polymorphisms in DNA repair and metabolic genes in bladder cancer.
S. Sanyal, F. Festa, S. Sakano, Z. Zhang, G. Steineck, U. Norming, H. Wijkstrom, P. Larsson, R. Kumar, and K. Hemminki (2004)
Carcinogenesis 25, 729-734
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Interaction of human and bacterial AlkB proteins with DNA as probed through chemical cross-linking studies.
Y. Mishina, C.-H. J. Lee, and C. He (2004)
Nucleic Acids Res. 32, 1548-1554
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Expression of Base Excision DNA Repair Genes Is a Sensitive Biomarker for in Vivo Detection of Chemical-induced Chronic Oxidative Stress: Identification of the Molecular Source of Radicals Responsible for DNA Damage by Peroxisome Proliferators.
I. Rusyn, S. Asakura, B. Pachkowski, B. U. Bradford, M. F. Denissenko, J. M. Peters, S. M. Holland, J. K. Reddy, M. L. Cunningham, and J. A. Swenberg (2004)
Cancer Res. 64, 1050-1057
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Deficient Nucleotide Excision Repair Capacity Enhances Human Prostate Cancer Risk.
J. J. Hu, M. C. Hall, L. Grossman, M. Hedayati, D. L. McCullough, K. Lohman, and L. D. Case (2004)
Cancer Res. 64, 1197-1201
   Abstract »    Full Text »    PDF »

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