DNA Repair MMR Colon Cancer

Mutation Research 736 (2012) 82 92

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Mutation Research/Fundamental and MolecularMechanisms of Mutagenesis

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Review

Oxidatively damaged DNA and its repair in colon carcinogenesis

Barbara Tudeka,b, Elzbieta Speinaa,

a Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Polandb Institute of Ge

a r t i c l

Article history:Received 9 JanReceived in reAccepted 16 AAvailable onlin

Keywords:Colorectal canOxidative streLipid peroxida8-Oxo-7,8-dihEtheno DNA adDNA repair patients is signicantly increased; however, excision rate is regulated separately, being increased for 8-

oxoGua, while decreased for lipid peroxidation derived ethenoadducts, Ade and Cyt; (iii) excision rateof Ade and Cyt in colon tumors is signicantly increased in comparison to asymptomatic colon margin,and ethenoadducts level is decreased. This review highlights mechanisms underlying such deregulation,which is the driving force to colon carcinogenesis.

2012 Elsevier B.V. All rights reserved.

Contents

1. Introd2. Histop3. Oxida

3.1. 3.2. 3.3.

4. Repai4.1. 4.2.

5. Aberr6. Concl

ConiFundiRefere

Abbreviatiposis coli; FapBER, base excietheno-2-deo

CorresponE-mail add

0027-5107/$ http://dx.doi.ouction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83athology of CRC and mutations in critical genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83tive stress in the development of colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Consumption of red meat and alcohol and tobacco smoking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

r of oxidative DNA damage as a driving force to colon carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85Repair of 8-oxo-7,8-dihydro-2-deoxyguanosine in colon adenoma and carcinoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86Repair of etheno DNA adducts in colon carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

ant repair of oxidatively damaged DNA bases and mutations in critical genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88usions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89ct of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90ng. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90nces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

ons: 8-oxodG, 8-oxo-7,8-dihydro-2-deoxyguanosine; 8-oxoGua, 8-oxo-7,8-dihydroguanine; AD, adenoma; CRC, colorectal cancer; APC, adenomatous poly-yGua, 2,6-diamino-4-hydroxy-5-formamidopyrimidine; APE1, apurinic site endonuclease 1; ROS, reactive oxygen species; RNS, reactive nitrogen species;sion repair; Ade, 1,N6-ethenoadenine; dA, 1,N6-etheno-2-deoxyadenosine; Cyt, 3,N4-ethenocytosine; dC, 3,N4-etheno-2-deoxycytidine; 1N2-dG, 1,N2-xyguanosine; LPO, lipid peroxidation; MMR, mismatch repair.ding author. Tel.: +48 22 592 3334; fax: +48 22 592 2190.ress: [email protected] (E. Speina).

see front matter 2012 Elsevier B.V. All rights reserved.rg/10.1016/j.mrfmmm.2012.04.003netics and Biotechnology, Faculty of Biology, Warsaw University, Pawinskiego 5a, 02-106 Warsaw, Poland

e i n f o

uary 2012vised form 2 April 2012pril 2012e 25 April 2012

cersstionydroguanineducts

a b s t r a c t

Inammation, high fat, high red meat and low ber consumption have for long been known as the mostimportant etiological factors of sporadic colorectal cancers (CRC). Colon cancer originates from neoplas-tic transformation in a single layer of epithelial cells occupying colonic crypts, in which migration andapoptosis program becomes disrupted. This results in the formation of polyps and metastatic cancers.Mutational program in sporadic cancers involves APC gene, in which mutations occur most abundantlyin the early phase of the process. This is followed by mutations in RAS, TP53, and other genes. Pro-gression of carcinogenic process in the colon is accompanied by augmentation of the oxidative stress,which manifests in the increased level of oxidatively damaged DNA both in the colon epithelium, andin blood leukocytes and urine, already at the earliest stages of disease development. Defence mecha-nisms are deregulated in CRC patients: (i) antioxidative vitamins level in blood plasma declines withthe development of disease; (ii) mRNA level of base excision repair enzymes in blood leukocytes of CRC

B. Tudek, E. Speina / Mutation Research 736 (2012) 82 92 83

1. Introduction

Colorectal cancer (CRC) is one of the most frequent causes ofdeath in Western countries. The cases are roughly equally dis-tributed bepathogeneswhich incretions in crit

Inammof reactive of nucleic amutagenic

The geneciency in mphenotype instability colon carcibe associatposis coli) signaling pof APC prowell describlesions whilife. The prpolyps is cluated formage of onse1015% of quently, in a biallelic mMutY is a DDNA of ade(8-oxoGua)pathologicagenerative review focucolon carcitiation (genmolecular son the dereresponse an

2. Histopa

A singleand rectumtially increastem cells atypes, absolial cells. Thdifferentiatthe colonicfrom the crincreases una single probowel wall of colon cantions colonmain typesbut not by hyperplastimal morphthe basemetendency toplastic, has

epithelial cells are observed; the nuclei of the epithelial cells arelarger than normal, and their position within the cells is often aber-rant. Crypts crowd together in kaleidoscopic pattern. As adenomasgrow in size, they become more dysplastic. They are also more likely

tain cryps advely troun

or ts ares; theyps a

How obseina

s ares, cae fouarcinmor

secuing mand/omor enes tatedfrequ

stagetic cnetiche ehe ea

themas

freqas as a

syste wh

ivatoiptio

sevenes eP-7)/rowors, 1. Transcr

[14]mulaons AS, Bl, an. K-Ras a

d in growgene. Losr stimnoma

coloro o

ffect tween the sexes. Two main factors are considered inis of this cancer: (i) inammation and high fat diet [1],ases the number of lesions in DNA and induces muta-ical genes; and (ii) genetic predispositions.ation is associated with the release of large amountsoxygen and nitrogen species [2] leading to oxidationcids, proteins and lipids, and induction of several pro-DNA lesions.tic predisposition to CRC may be connected to the de-ismatch repair system (MMR), which causes mutatorof intestine cells (manifesting itself as microsatellitesMSI) and development of hereditary non-polyposis

noma HNPCC (or Lynch syndrome). They may alsoed with the deciency of the APC (adenomatous poly-gene product, which functions are related to Wntathways and migration of intestine epithelium. Lacktein leads to familial adenomatous polyposis (FAP), aed syndrome characterized by multiple adenomatousch usually appear in the second and third decades ofobability of malignant transformation of one of theose to 100% [3]. A subset of patients present an atten-

(AFAP) characterized by fewer lesions (

84 B. Tudek, E. Speina / Mutation Research 736 (2012) 82 92

Fig. 1. Aberra t opemethylene blu ); (B and eosin (ma

extent of DNSection 5).

3. Oxidativ

The majcolon cancewhich is dewith insufdefence [15DNA damaggression of for the devconsumptiostimulate th(LPO) [1,19moderate cical processall compon

3.1. Inamm

Epidemiare linked of inammainammatioand RNS [2dation of pounsaturatedare relativechain reacti2-alkenals (2-alkenals ( HNE) andoxal, 4-oxois tremendoseveral of th

Reactiveteins [22],

tivesepox

prorogeammlooxyserv

tissuheliat in aultiary

overatic ropotion nt crypt foci. (A) A view from the lumen site of intact mouse colon. The colon was cue. The mucosal side was observed under the light microscope (magnication 100gnication 1000).

A damage, and potential of gaining new mutations (see

e stress in the development of colon cancer

ority of pathological factors favoring development ofr involve induction of oxidative stress in the colon,ned as overproduction of oxygen species combinedciency in protective mechanisms of anti-oxidative,16]. Oxidative stress is involved in the production ofe and mutations associated with the initiation or pro-human cancers [17,18]. The main pathological factorselopment of CRC are inammation, fat metabolism,n of meat and alcohol and tobacco smoking. All thesee release of ROS and RNS as well as lipid peroxidation]. These compounds play a dual role in cells. At low or

derivaity of than toof hyding inas cycwas obcancerin epitbut noMin (mmammCOX-2enzymbeen ppromooncentrations they are mediators of specic physiolog-es, whereas high concentrations can be detrimental toents of the cell.

ation

ological studies suggest that inammatory processeswith CRC. This is true particularly in the associationtory bowel disease and colorectal cancer [20]. Duringn activated macrophages release large amounts of ROS

], which oxidize nucleic acids, proteins and lipids. Oxi-lyunsaturated fatty acids generates reactive aldehydes

in , -positions which, in contrast to ROS and RNS,ly stable and can diffuse throughout the cell [19]. Shortve aldehydes are classied into the following families:e.g., acrolein, crotonaldehyde, 2-hexenal), 4-hydroxy-e.g., 4-hydroxy-2-hexenal HHE, 4-hydroxy-2-nonenal

ketoaldehydes (e.g., malondialdehyde MDA, gly--2-nonenal ONE) [21]. Multiplicity of LPO productsusly augmented by the existence of stereoisomers ofese compounds.

aldehydes either react directly with DNA and pro-or undergo further oxidation to more reactive epoxy

suppressionsis [2931]metabolismtion of heptare highly pathways cmutations oof COX-2 byence appea[33,34].

3.2. Consum

Epidemihigh intakeincreased rsuggest thaof colonic heme oxyginhibitor, zia comet asstion [35]. TThe preincn along the longitudinal median axis, formalin xed and stained withand C) cross sections of mouse epithelium stained with hematoxylin

, such as 2,3-epoxy-4-hydroxynonanal [23]. The afn-idized LPO products to nucleic acids is much higherteins. Epoxidation of enals may occur in the presencen peroxide, but is also catalysed by enzymes produc-atory mediators, prostaglandins and leukotrienes, suchgenase-2 (COX-2) and lipooxygenases (LOX) [24]. Ited that COX-2 is overexpressed in 80% of colorectales [25,26]. Increased levels of COX-2 were observedl cells, inammatory cells, as well as in stromal cells,djacent normal tissues [27]. COX-2 overexpression inple intestinal neoplasia) mice was sufcient to inducetumors [28]. The mechanism of tumor induction byexpression is complex, and involves the activity of itsend-products, prostanoids. A number of theories havesed to explain the role of tumor-derived prostanoids inof angiogenesis, induction of tumor cell proliferation, of immune response, and protection against apopto-. Additionally, it was shown that arachidonic acid (AA)

mediated by COX-2 and 5-LOX results in the forma-anone-etheno (H)-DNA adducts. The H-DNA adductsmutagenic in mammalian cells suggesting that theseould be (at least in part) responsible for the somaticbserved in tumorigenesis [32]. That is why inhibition

non-steroid anti-inammatory drugs or RNA interfer-red a successful approach in colon cancer prevention

ption of red meat and alcohol and tobacco smoking

ological and animal model studies have suggested that of heme, present in red meat, is associated with anisk of colon cancer. Recently elucidated mechanismst heme induces DNA damage and cell proliferationepithelial cells via hydrogen peroxide produced byenase. In Caco-2 cells the presence of heme oxygenasenc protoporphyrin, reduced DNA damage (measured byay) triggered by hemin as well as cell hyperprolifera-he effect of heme may be modied by LPO products.ubation of colon adenocarcinoma, SW480, cells with


hemoglobin (Hb) and its subsequent exposure to linoleic acidhydroperoxides (LAOOH) led to an increase in cell death, malon-dialdehyde formation, and DNA fragmentation and these effectswere related to the peroxide group and the heme present inHb. SW480level of thedeoxyguanowith Hb ledrelated witbowel bleedenhancer oquence con[36].

Anotheris chronic contribute action of aalcohol metion of ethaand duringdeoxyguano[38]. Both tlipid peroxiZucker ratsthe liver DNwas correla[40]. Thus, odG, 1,N2-associated w

The resuwith the riare controvAlthough inincreased tbase, 8-oxo8-oxoGua lwas observ

3.3. DNA da

Oxidativlogical chan[43,44]. DNneous groumolecules pA plethora genetic materties [45]. biomarker oesis [46]. T(8-oxodG) 8-OxodG isacids or capolymeraseoxidation a

LPO prodextent as dear and cycDNA with g[1,2]purinear N6-(3-ooxopropenyM1dG is theand rodent to T and tra8-oxoGua [

Exocyclic propano DNA adducts are formed by the attachmentof unsaturated reactive aldehyde to ring and extra-ring nitrogenatoms in DNA bases, which generates additional saturated, six-membered ring in a DNA base. These adducts are derived from the

n of -dG

]. Ethed toknowtion into e or enosubs, deplic Dd exhe ine rel].ateddisead ul

]. Thiiolog

air ocarci

maj excied bmilyassicii) exal ofpatholyml DNagefromtly, 1ppinglly tunctsic (A(APE

have3 toe. Th, 8-oxoGuorpo

8-oua iTP todieons. DNA odG

NA bohy-Oxod re

corre cells treated with Hb and LAOOH presented a higher modied DNA bases 8-oxoGua and 1,N2-etheno-2-sine (1,N2-Gua) compared to the control. Incubations

to an increase in intracellular iron levels, which cor-h DNA oxidation. Thus, Hb from either red meat oring caused by inammatory processes could act as anf fatty acid hydroperoxide genotoxicity, and in conse-tribute to the accumulation of DNA lesions in colon cells

frequently suggested risk factor for CRC developmentalcohol consumption. One of the factors which mayto the development of alcohol-associated cancer is thecetaldehyde, the rst and most toxic metabolite oftabolism [37]. Acetaldehyde is produced by the oxida-nol by hepatic NAD-dependent alcohol dehydrogenase

threonine catabolism. Acetaldehyde reacts with 2-sine in DNA to form 1,N2-propanodG and 1,N2-dGhese DNA lesions were described to derive also fromdation [39,36]. In hepatic cancer model, lean and obese

higher levels of etheno DNA adducts were observed inA of alcohol-fed than in control animals. This increaseted with the induction of cytochrome P-450 isoform 2E1the formation of exocyclic DNA adducts, like propan-dG, dA and dC may be the important mechanismith acetaldehyde related cancer risk.

lts of epidemiological studies also link tobacco smokingsk for CRC development. However, the obtained dataersial, and the molecular mechanism remains unclear.

the leukocytes of lung cancer patients tobacco smokinghe level of one of the major oxidatively damaged DNAGua [41], in CRC patients no effect of tobacco smoking onevel in the leukocytes and 8-oxoGua urinary excretioned [42].

mage

ely damaged DNA has been blamed for the physio-ges associated with degenerative diseases and cancerA damage caused by free radicals is the most heteroge-p of DNA lesions due to the wide variety of deleteriousroduced in cells in the conditions of oxidative stress.

of damaged DNA bases are formed upon ROS attack onerial, several of them reveal strong promutagenic prop-One of the major and best studied is 8-oxoGua, a typicalf oxidative stress, which may play a role in carcinogen-he presence of 8-oxo-7,8-dihydro-2-deoxyguanosineresidues in DNA leads to GCTA transversions [47].

formed in DNA either via direct oxidation of nucleicn be incorporated from the nucleotide pool by DNAs, the latter process being an important source of DNAnd genome instability [48,49].ucts may contribute to DNA damage to nearly the sameirectly oxidized bases. There are distinct groups of lin-lic LPO specic DNA lesions. Malondialdehyde reacts inuanine, adenine and cytosine to form cyclic pyrimido-e-10(3H)-one-2-deoxyribose (M1dG) adduct and lin-xopropenyl)-2-deoxyadenosine (M1dA) and N4-(3-l)-2-deoxycytosine (M1dC) adducts, respectively [50].

major MDA-DNA adduct and was detected in humantissues. In Escherichia coli cells, it induces transversionsnsitions to A with a frequency comparable with that of15].

reactiodG, Cro[51,52attachis not exposiduced chloridand ethare unlengthexocycstituteWith tand ar[54,55

Elevcolon ease an[20,56CRC et

4. Repcolon

Theis basedamagAlkB faIn a cltion, (removof the DNA porigina

Damexcise Presenoverlanisticamonofan abaclease whichbonds enzymlesions

8-Oits incexcises8-oxoGoxodGthis momutatidirect of 8-oxinto Dphosph[61]. 8dase andirect DNA with, e.g., acrolein, crotonaldehyde and HNE. Acr- and HNE-dG were found in rodent and human tissueseno DNA adducts posses ve-membered exocyclic rings

DNA bases. The exact pathway of their formation in vivon, although it is clear that they are generated by the

of DNA to lipid peroxides. Ethenoadducts are also intro-DNA by certain environmental carcinogens like vinylits metabolite, chloroacetaldehyde (CAA) [53]. Propano--type adducts that are found in native mammalian DNAtituted and substituted with side chains of differentending on the structure of reacting LPO product. AllNA adducts have strong miscoding potential. Unsub-ocyclic DNA adducts are more mutagenic than toxic.crease of the side chain the toxic properties increaseated to the inhibition of replication and transcription

levels of dA and dC were found in pro-carcinogenicses, like inammatory bowel disease, Crohns dis-cerative colitis, and in addition in chronic pancreatitiss suggests that LPO-derived DNA lesions contribute toy.

f oxidative DNA damage as a driving force tonogenesis

or pathway for repair of oxidatively derived DNA lesionssion repair system (BER). Although several oxidativelyases are also repaired by mismatch repair system and

dioxygenases, this review will focus on BER activity.al view BER consists of ve steps: (i) lesion recogni-cision of the damaged base, (iii) AP site incision and

the chemical residues that could block further stepsway, (iv) incorporation of the proper nucleotide(s) byerases and (v) ligation of the DNA strand to restore theA molecule [5760].d bases are recognized by DNA glycosylases, which

DNA a wide range of oxidized and alkylated bases.3 human DNA glycosylases with different, but partially

substrate specicity have been identied. Mecha-wo types of DNA glycosylases can be distinguished,ional enzymes, that excise damaged base leaving behindP) site, which is subsequently cleaved by AP endonu-1) 5 to the AP site, and bifunctional DNA glycosylases,

endowed AP lyase activity that incises phosphodiester the AP site created by the glycosylase activity of theis review will focus on repair of three oxidative DNAxoGua, Ade and Cyt.a is repaired by a three-step system, which (i) lim-

ration of 8-oxodGTP into DNA during replication, (ii)xoGua from DNA, and (iii) corrects the base opposite ton DNA. Different DNA polymerases can incorporate 8-

the DNA, and replicative DNA polymerases incorporated nucleotide usually opposite dA, generating A:T C:GApproximately a half of 8-oxodG in DNA arises from theoxidation, and the other half is a result of incorporationTP during DNA synthesis. Incorporation of 8-oxodGTPy DNA polymerases is limited by the activity of MTH1drolase, which hydrolyzes 8-oxodGTP to 8-oxodGMPdGMP is subsequently dephoshorylated by nucleoti-moved from the cell [62]. Many observations indicate alation between 8-oxodG formation and carcinogenesis


in vivo [46,6366]. The second line of defence is glycosylase MutY(MYH) that removes adenine paired with 8-oxoGua. Activity of thisenzyme prevents mutations G:C T:A, when dATP is incorporatedopposite 8-oxoGua during replication [67]. After removal of Adeby MYH glycosylase, repair DNA polymerase incorporates dCMPopposite 8-ponent of thlyase is theDNA, but onactivity of tthe glycosyreplication which excitively [72].induced by is induced the pool of and OGG1 gto colon canof several m(exon 7) andA:8-oxodGquency. The[73].

Several described, wphic Cys326activity, bocleotides [7from -irra[74,76]. It walleles mayryngeal cancancer wasa decreasehead and nrate and siin cellular the acquisiSuch an idpro-oxidancancer.

Ade is ewhereas Cexcises thy5-methylcystranded uglycosylaseislands [88,

ANPG gbesides Ahypoxanthimethylguanwith guaninext enzymTDG and A[9295].

Ethenocon the levelbut also on primary subCyt, and aallow its exThis may edifferent hu[19].

Table 1mRNA level of DNA glycosylases (OGG1, ANPG and TDG) and APE endonuclease(APE1), and MTH1 phosphohydrolase in relation to 18S rRNA (106) in leukocytesof CRC and AD patients and healthy controls.

mR

CRC

1.2(0.7n = 12.(4.0n = 7.9(1.8n = 88.(42n = 86.(5.1n =

fromvely.cts wpariso

CRC lues a

pair a an

rderpair n caof diped rs of nd pease

AD leveidant

bloo to hd plaeasin

by the fact that urinary level of 8-oxodG was augmented in AD patients, but 8-oxoGua level was enhanced only inut not in AD individuals [42]. Urinary 8-oxodG may reection of nucleotide pool, while 8-oxoGua reects rather oxi-

of DNA. Since nucleotide pool is much more susceptible toion than dsDNA, 8-oxodG in urine may be a more sensitiveor of oxidative processes in the body, and shows that evenindividuals the oxidative processes are enhanced. The sug-

mechanisms responsible for the oxidative stress in cancerts include [43]: (i) granulocyte activation with release of ROS;ulation of cytokines, of which some, e.g., tumor necrosis

produce large amounts of ROS; (iii) production of hydrogende by malignant cells, which in advanced stages of cancere released into the blood stream and penetrate into other

[2].restingly, we also observed an increase of mRNA levels ofenzymes, OGG1, APE1 and MTH1 in leukocytes of CRC andividuals (Table 1) [42]. Expression of APE1 and OGG1 genesown to be induced by ROS [97], and this could explain induc-

repair enzymes transcription in leukocytes of CRC and ADuals. On the other hand induction of repair enzymes may beof a carcinogenic program, which might decrease apoptosisoxodG. Then 8-oxoGua can be excised by the third com-e system, OGG1 glycosylase [68]. OGG1 glycosylase/AP

major enzyme catalyzing excision of 8-oxoGua fromly when paired with Cyt or Thy [69,70]. The AP lyasehe OGG1 protein is about 10-fold lower than that oflase [71]. When 8-oxodGTP is included into DNA duringit is probably removed by NEIL1 or NEIL2 glycosylases,ses 8-oxoGua paired with dC/G/T/A or dC/A, respec-

This complex three-tier system prevents mutationsthe presence of 8-oxodG in DNA, both when this lesiondirectly in the DNA, and when it is incorporated fromnucleotides during replication. Polymorphisms of MYHlycosylases are related to modulation of susceptibilitycer. MYH variations signicantly increase CRC risk, andutations described, two are the most prevalent: Y165Cd G382D (exon 13). Mutated enzyme excises Ade from

pair with a decreased rate, increasing mutation fre- association of MYH with CRC was rst reported in 2002

polymorphic changes in the OGG1 gene have beenith the most common being Ser326Cys [74]. Polymor-

OGG1 protein was found to have a lower enzymaticth when 8-oxoGua was excised from oligodeoxynu-5], and when 8-oxoGua and FapyGua were liberateddiated DNA by puried Cys326 or Ser326 OGG1 enzymeas suggested that the presence of two OGG1 326Cys

confer an increased risk of lung, prostate and nasopha-cer [7779], but no association with the risk for colon

found [80,81]. Our and other functional studies report in 8-oxoGua excision rate in lung [41,82,83] andeck cancer patients [84]. Such a decrease in excisionmultaneous increase in 8-oxodG and FapydG levelsDNA favors a pro-oxidant state and may acceleratetion of mutations in critical genes leading to cancer.ea is basically derived from the observation that at environment is characteristic for advanced stages of

xcised by alkylpurine-DNA-N-glycosylase (ANPG) [85],yt by thymine-DNA glycosylase (TDG); the latter alsomine from G:T pairs, resulting from deamination oftosine [86]. Ethenocytosine is also excised by single-racil DNA glycosylase, SMUG1 [87] and by MBD4, although activity of the latter is strongly limited to CpG89].lycosylase has a wide substrate specicity, andde excises from DNA also 1,N2-ethenoguanine [90],ne and the alkylated bases, 3-methyladenine and 7-ine [85]. TDG excises Cyt, Thy and Ura from pairsne, and its activity is strongly stimulated by thee in the BER pathway, AP endonuclease, APE1 [91].PE1 also play the role of transcription regulators

ytosine repair by the BER system is dependent not only and activity of TDG, MBD4 or SMUG1 DNA glycosylases,the presence and/or activity of ANPG glycosylase, whichstrate is Ade. ANPG binds strongly to DNA containinglthough does not excise this modied base, does notcision by the proper Cyt glycosylase, like TDG [96].xplain observation that the level of Cyt measured inman tissues was constantly higher than that of Ade

OGG1

ANPG

TDG

APE1

MTH1

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Interepair AD indwas shtion ofindivida part NA level (arbitrary units)a p

patients (C) AD patients (A) Controls (H)

8 0.99 0.19


A

50

60

70

80

90

100

* * *

CRC patients

Controls

n = 68

B

0

10

20

30

40 n = 90

8-o

xo

Gu

a e

xcis

ion

activity

(p

mo

ls/h

/mg

pro

tein

)

100

110

120

*

* * * CRC patients Controls

1

2

3

4

5

6

7

8

90

8-o

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Gu

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xcis

ion

activity

(pm

ols

/h/m

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rote

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Fig. 2. The meof CRC patientdistinguished p < 0.005; *, p 0.0000 (C vs. H)33 (34), (18)d >0.079 (A vs. H)1 (1), (1)e >0.0000 (C vs. A)

0.820.18

e distribution analysis).


40

45

50 * * * a

ctivity

g p

rote

in)

CRC pati ents

C ontrols

AE

xcis

ion

(pm

ols

/h/

B

Excis

ion

activity

(pm

ols

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g p

rote

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Fig. 3. (A) Thleukocyte DNA(MannWhitnexcision rate ip < 0.001 (Wilc

Derived from [

compared t(Fig. 3A) [1Ade and asymptomaCRC patientin controls,to be lowergests that thmultifactortissues.

The lowpatients wagenes nor tTDG glycoscontrary, mhigher in PThus directby inammmore likelyshown to bgen peroxidAs shown fosistent oxidalready dur[111]. A nuof several robserved loous lower l

may thus suggest that other mechanisms are up-regulated in CRCpatients and determine the level of etheno adducts in DNA. Otherrepair systems engaged in etheno adducts elimination from DNA

e, e.g., oxidative demethylation by AlkB family proteins ortide ntereyt erounes ltudis thanive c,116]betw3) [er, dl typeA levent wer fordernd c colylasetissur APly alC geay inownN1 enPC ex25

30

35 n = 56

54=

0

5

10

15

20

n = 56n = 54

*

Ade Cyt

n

14

16

n = 54

* * * Tumor Normal colo n

0

2

4

6

8

10

12

n = 54

n = 54

n = 54

* * *

Ade Cyt

e mean and standard deviation of Ade and Cyt excision rate in

includnucleo

Of iand Cthe sur23 timother stumorulceratsis [56found p = 0.01howevseverathe dconsistbe high

In oAde atomatiglycoscolon only foprobabthe APtein mwas shand FEwith A of CRC patients and control individuals. ***, p < 0.001; *, p < 0.05ey U test). (B) The mean and standard deviation of Ade and Cytn colon tumor and normal surrounding tissues of CRC patients. ***,oxon rank sum test).

105] with permission from Elsevier.

o controls matched for age, sex and a smoking habit05]. However, in colon tissues, excision activities forCyt were signicantly higher in tumor than in adjacent,tic colon tissue (Fig. 3B) [105]. In leukocytes (PBL) ofs dA and 1,N2-dG level was unexpectedly lower than

and the level of dA and dC also showed a tendency in tumor than in normal colon tissue [105]. This sug-e regulation of etheno adduct level and repair may be

ial and may differ in target (colon) and surrogate (PBL)

er excision rate for Ade and Cyt in leukocytes of CRCs not linked to mutations in exons of ANPG and TDGo down regulation of mRNA expression of ANPG andylases or its BER activator, APE1 endonuclease; in theRNA levels of these repair enzymes were signicantlyBL of CRC than in healthy controls (Table 1) [42,105].

inactivation/inhibition of repair enzymes activitiesatory mediators released in the blood stream is a

explanation. Indeed, several DNA repair enzymes weree directly inhibited by nitric oxide [106108], hydro-e [109] and LPO product, 4-hydroxynonenal [55,110].r several human cancer sites and animal tumors, per-ative stress and LPO-induced DNA damage increaseding premalignant stages in a time-dependent mannermber of studies demonstrated increase of mRNA levelepair enzymes upon oxidative stress [97,112,113]. Thewer Ade and Cyt excision (Fig. 3A) and simultane-evel of etheno adducts in PBL of cancer patients [105]

In conclactivity of compared tings, that tPBL from Cmechanistiticularly Cstages in thin critical gsylase remoinduction odeaminatio

5. Aberranmutations

Activity naling moleAPC and TP5repair rate events withBER proteinlation of ge

Mutatioesis, and areThe most frpart of the with DNA psuggested, Aproteins onBER (Fig. 4)protein an aactivity of Aexcision repair [114,115].st are the ndings in tumorous colon tissue. The Adexcising activities were much higher in tumor than inding normal colon (Fig. 3B) and was consistent with aower dA and dC adduct levels [105]. Also in severales lower level of dA and dC was observed in colon

in colon tissues of cancer prone patients suffering fromolitis, Crohns disease or familial adenomatous polypo-. In our study in normal colon a negative correlation waseen dC level in DNA and its excision rate ( = 0.64,105]. This supports a role of BER in Cyt-elimination;oes not exclude other etheno adduct control systems. Ins of non tumorous human tissues previously analyzed,el in DNA was found to be lower than that of dC [111],ith our observation that excision activity was found tor Ade than for Cyt (Fig. 3) [105].

to understand a huge increase of excision activity ofCyt in colon tumor tissue in comparison to asymp-on margin, we measured mRNA level of ANPG and TDGs, as well as APE1 endonuclease in tumor and normales. Higher mRNA level in tumor tissue was observedE1 [105]. APE1 stimulates Cyt excision [91], and mostso Ade. Another possibility are frequent mutations inne in colon tumors [117]. APC tumor suppressor pro-hibit BER engaged in repair of Ade and Cyt since it

that it can directly interact with DNA polymerase donuclease [118]. BER activity was inversely associatedpression in several breast cancer cell lines [119].usion, we have shown, for the rst time, that excisionAde and Cyt is lower in PBL of CRC patients wheno healthy individuals. However, our unexpected nd-he level of dA and 1,N2-dG was lower in DNA ofRC patients than in healthy controls currently remainscally difcult to explain. If such etheno adducts, par-yt excision deciency also occurs during premalignante target organ, still may favor acquisition of mutationsenes leading to neoplastic transformation. TDG glyco-ves Thy and Ura paired with guanine, and may preventf mutations caused by cytosine and 5-methylcytosinen [120].

t repair of oxidatively damaged DNA bases andin critical genes

and expression of BER proteins is modulated by two sig-cules, which are frequently mutated in colon cancer, the3 gene products. Thus, mutations in these genes affectof oxidatively damaged DNA, and favor pro-mutagenicin colon epithelial cells. On the other hand at least threes, namely, APE1, TDG and OGG1 take part in the regu-ne expression.ns in the APC gene are early events in colon carcinogen-

found in about 80% of colon adenomas and carcinomas.equent mutation results in truncation of the C-terminalAPC protein. Wild type APC protein directly interactsolymerase , FEN1 endonuclease [118], and as recentlyPE1 endonuclease [121] inhibiting the assembly of BER

damaged DNA and the activity of short and long patch. In LoVo, colon cancer cells expressing truncated APCccelerated assembly of BER proteins, as well as higherPE1, FEN1 and Pol were observed [121]. Activation of


APE1/

ANPG

+

Genome

instability Progression

+

Genome

instabilityProgression

Fig. 4. The in me stactivity and tr nced BAPE1 activity APE1,interacts with scripregulated by c erationand may favor ted anin circle denot e ; Falkyladenine D sylasedeaminase; HI

APE1 may which are about 50% oof APE1 tra[122]. On tby TP53 inh[123]. ThusAPE1 amou

Increasepathway, asion: in inpatients (atDNA adducincreased, arelated witSimilarly, inAPE1 was a

APE1, beregulatory participatesstages of Caccumulatiinstability wgrowth (Fig

IncreaseDNA glycossusceptiblesites, and ADNA [91,12tion of promto hypomeinduction odeaminase Methylcytoby AID to tsubsequentfrom dT:dGreconstitutirecruiting pis engaged

pmelso d-uoeatmf mo

rom S-ph, exci

G1 ayc tationhylatdemehylat

the G, OlymPol FEN1

APE1

+TP53

APC

mutated +

+

TDG/MBD4

OGG1

mutated +

++

HIF-1Angiogenesis

Erythropoesi s

uence of APC and TP53 genes mutations on the activity of BER enzymes and genoanscription, respectively, and up-regulate BER. Increased APE1, ANPG and unbalamay also accelerate the excision rate of DNA glycosylases, OGG1 and TDG/MBD4.

the deaminase AID and may favor demethylation of promoters and induction of tran-Myc and estrogen receptors, and thus may contribute to acceleration of cell prolif

genomic instability and cancer progression. APE1 also participates in HIF-1 mediaes stimulation or increase; APC, adenomatous polyposis coli; Pol , DNA polymerasNA N-glycosylase; OGG1, 8-oxoGua DNA N-glycosylase; TDG, thymine DNA N-glycoF-1, hypoxia-inducible factor 1 subunit.

also occur as a consequence of TP53 gene mutations,late, but frequent events in colon carcinogenesis (inf cancers). TP53 protein participates in downregulationnscription in cells treated with DNA damaging agentshe other hand TP53 mediates ubiquitination of APE1ibitor, MDM2, and in consequence APE1 degradation, mutations in TP53 gene should additionally increasent in cancer cells.d APE1 activity may result in unbalancing of BERnd may favor genomic instability and cancer progres-amed non-cancerous colon tissues of ulcerative colitis

high risk for colon cancer, that accumulate high ethenots [124]), ANPG and APE1 activities were signicantlynd microsatellite instability (MSI) was positively cor-h their imbalanced activities of repair enzymes [125].

yeast and human cells over-expression of ANPG and/orssociated with frameshift mutations and MSI [125].sides DNA repair function, also plays a role of redox

develomay awith 5CRC trtance o5-FU fdelaysHence[129].

OGby c-MaccelerdemetLSD1 demetaround8-OxodRNA poprotein for several transcription factors. For example, in HIF-1 mediated angiogenesis [126]. Thus at lateRC development, mutations in TP53 gene will lead toon of APE1 protein, and in addition to increasing genomeill also favor angiogenesis and in consequence tumor

. 4).d APE1 activity may also accelerate the excision rate ofylases. TDG and OGG1 were shown to be particularly

to induction by APE1, since they bind strongly to APPE1 increases turnover of these enzymes on damaged7]. Increased activity of TDG may favor demethyla-oters of several genes and in consequence contribute

thylation of DNA observed in colon cancer [13] andf transcription of several genes. TDG interacts with theAID and the damage response protein GADD45a. 5-sine and 5-hydroxymethylcytosine are rst deaminatedhymine and 5-hydroxymethyluracil, respectively, andly TDG removes thymine and 5-hydroxymethyluracil

or 5OHMedU:dG pairs, which initiates BER and enableson of G:C base pairs [128]. TDG is also necessary for300 to retinoic acid (RA)-regulated promoters, andin transcriptional control of genes during embryonic

gets and stiOGG1 or Athat regulaing loops thloci [132]. Fin histone the downstget chromachromatin bthat bring tregulation o

6. Conclus

Oxidativcarcinogenand AD paexcision retranscriptiosues. Activinetwork, winactivationAID-media ted

demethyla tion of

gene promoter s

Transcription of

several gene s

Transcriptio n of

Myc-regulated

genes

Prolifera tio n

Progression

ability. Mutations in APC and TP53 proteins lead to increase in APE1ER pathway may favor genomic instability and cancer progression.

TDG and OGG1 take part in the regulation of gene expression. TDGtion of several genes. OGG1 and APE1 stimulate transcription of genes. Increased APE1 activity may result in unbalancing of BER pathway,giogenesis and erythropoesis and may favor tumor growth. + symbolEN 1, ap endonuclease 1; APE1, apurinic site endonuclease 1; ANPG,; MBD4, methyl-CpG binding domain protein; AID, activation-induced

nt. Its deciency is embrionaly lethal [120]. TDG statusetermine sensitivity of CRC patients to chemotherapyrouracil (5-FU), a chemotherapeutic routinely used inent. Inactivation of TDG signicantly increases resis-use and human cancer cells toward 5-FU. Excision ofDNA by TDG generates persistent DNA strand breaks,ase progression, and activates DNA damage signaling.sion of 5-FU by TDG mediates DNA-directed cytotoxicity

nd APE1 stimulate transcription of genes regulatedranscription factor [130], and thus may contribute to

of cell proliferation (Fig. 4). The mechanism involvesion of histone H3 by specic FAD-containing enzyme,thylase which generates hydrogen peroxide duringion [131]. In consequence a local oxidation of DNAE-boxes and TSS region of Myc target genes is triggered.GG1 and APE1 were found to be engaged on the sameerase II and Myc occupied chromatin regions of Myc tar-

mulate transcription of these genes. Silencing of eitherPE1 inhibits Myc mediated transcription. It is possibletory regions in a gene interact with each other form-at often bridge considerable distances on the genomicollowing Myc binding local demethylation of lysine 4H3 (H3K4me2) triggers recruitment of the OGG1 andream BER enzymes thus producing nicks on Myc tar-tin. This may relax the DNA strands and could favorending necessary for the formation of chromatin loopsogether RNAPII and Myc. OGG1 is also engaged in thef transcription from estrogen promoters [133].

ions

e stress is induced at the early, adenoma, stage of colonesis, and is increasing during disease progression. CRCtients reveal a huge increase of mRNA level of basepair enzymes in blood leukocytes. However, increasedn is not always correlated with repair capacity of tis-ties of BER enzymes remain under a complex regulativehich besides stimulation of transcription includes direct

by oxidation stress products, interaction with other


BER proteins, and with signaling molecules, which are frequentlymutated in colon cancer, that is APC and TP53 proteins. Mutatedproteins do not inhibit transcription and/or activity of base exci-sion repair enzymes. This increases the amount of repair enzymeswithin cellsDNA damagand may be

Conict of

The auth

Funding

Funded We thank al

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Oxidatively damaged DNA and its repair in colon carcinogenesis1 Introduction2 Histopathology of CRC and mutations in critical genes3 Oxidative stress in the development of colon cancer3.1 Inflammation3.2 Consumption of red meat and alcohol and tobacco smoking3.3 DNA damage

4 Repair of oxidative DNA damage as a driving force to colon carcinogenesis4.1 Repair of 8-oxo-7,8-dihydro-2-deoxyguanosine in colon adenoma and carcinoma patients4.2 Repair of etheno DNA adducts in colon carcinogenesis

5 Aberrant repair of oxidatively damaged DNA bases and mutations in critical genes6 ConclusionsConflict of interest statementFundingReferences

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