When there is an oxidative stress, the generation of the intracellular H2O2 gets increased which enhances the binding of NF1 to the JWA promoter region. The binding stimulates the transcription and translation of JWA. The protein product of JWA phosphorylates MEK and this again leads to the phosphorylation of ERK. JWA is found to regulate E2F1 which leads to the transcription of XRCC1. The interaction between JWA and XRCC1 is found to occur in the cytoplasm and the nucleus where the cells are prone to oxidative stress. XRCC1 helps in the transportation of the JWA from the cytoplasm in to the nucleus whereas the JWA regulates and stabilizes nuclear XRCC1 by preventing it from ubiquitination. During the oxidative stress, both the JWA and XRCC1 are taken to the damaged part of the DNA and this confirms their major role in the BER pathway .
Cigarette smoke mainly contains the carcinogens and the Reactive Oxygen Species (ROS) . The smoke contains the free radicals which is present in both the mainstream and sidestream smoke. It is present in both the gas and the tar phase. The tar phase contains more reductants like quinone when compared to that of the gas phase . ROS includes radicals of the oxygen such as the superoxide and the hydroxyl radicals and some of the oxygen derivatives which lack unpaired electrons like hydrogen peroxide and hypochlorous acid. Polycyclic aromatic hydrocarbons, aromatic amines and N-nitroso compounds are some of the carcinogens present in the cigarette smoke which damages the DNA by forming the adducts. The enzymatic reactions carried out by the bacteria and inflammatory cells revealed that N-nitroso compounds present in cigarette smoke produces nitric oxide radicals which causes the oxidative damage and the accumulation of ROS leads to the oxidative stress which results in the cancer. ROS damages the DNA directly or indirectly by inducing lipid peroxidation and the oxidation of the protein. The indirect damage of the DNA includes the inactivation of the target enzymes which gets involved in the synthesis of the DNA whereas the direct damage of the DNA includes the strand breaks of the DNA, formation of the abasic sites and base adduct formation like thymine glycol, 5-hydrozymethyluracil and 8-hydroxy-2-deoxyguanosine. Damages in the base of the DNA and the single strand breaks in the DNA can be repaired by the BER pathway .
Free radicals in Skin cancer
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The cigarette smoke contains the free radicals which help in the lipid peroxidation. It mainly participates in the oxidation of Squalene (SQ), which is one of the important constituent of the human skin surface lipid in to the squalene monohydroperoxide (SQHPO). The oxidation of the human skin by the cigarette smoke is a very tedious process. It involves two types of oxidation. The first type is the oxidation of lipids to the corresponding hydroperoxides and the second type involves the oxidation of the hydroperoxides. It is also found that the hydroperoxides present on the human skin which can be detected by the chemiluminescence (CL) detector is oxidized more when compared to the one which is not exposed. The oxidation can be prevented by treating it with the antioxidants like glutathione, thiotaurine, hypotaurine and ascorbic acid . The accumulation of the squalene mono hydroperoxide on the surface of the skin causes the skin cancer .
Benzene in Leukemia [44, 45, i, k, l, m, n, o]
Benzene which is present in the cigarette smoke is not itself a toxic substance. It is converted in to a metabolite by the hepatic metabolism which travels to the bone marrow and there it exerts its toxic effect. The potential carcinogen benzene gets activated in the bone marrow and is converted to primary metabolites which includes the phenolic compounds like hydroquinone, catechol and trans-trans-muconic acid. The concentration of the three phenolic compounds will be increased in the bone marrow and especially the accumulation of hydroquinone and catechol will be of higher concentration. The hydroquinone which is a primary metabolite is converted in to the secondary metabolite 1,4-benzoquinone with the help of the enzyme myeloperoxidase and 1,4-benzoquinone is found to exert its toxic effect in the bone marrow by inducing the DNA damage [32, 36].
Fig.6. Benzene and its phenolic metabolites
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NNK in oesophageal cancer [43, i]
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a group 1 carcinogen which causes the esophageal cancer. NNK is a procarcinogen which is activated by the enzyme CYP1A1 present in the liver. The activated carcinogen gets involved in the process of methylation and pyridyloxobutylation. The methylated adducts of XRCC1 includes two pathways. First pathway includes the α-hydroxylation of NNK, a process in which the carbon next to the nitroso group gets hydroxylated and this leads to the formation of the diazohydroxide intermediate which binds to the DNA to from methyl adducts. Second pathway includes the process in which the NNK is converted to the carbonyl reduction product, NNAL that undergoes glucuronidation to form NNAL-Gluc. NNAL-Gluc is found to be excreted in human urine. The NNAL also undergoes α-hydroxylation, a process in which the carbon next to the nitroso group gets hydroxylated and this leads to the formation of the diazohydroxide intermediate which binds to the DNA to from methyl adducts. Adduct formed by the methylation includes 7-methylguanine (7mG), O6-methylguanine (O6-mG) and O4-methylthymine (O4-mT) which causes the G to A transition. The activated NNK also undergoes pyridoxobutylation and forms the pyridyloxobutylating intermediates which bind to the DNA to from pyridyloxobutyl adducts. The pyridyloxobutyl adducts include 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (7-pobdG), O2- [4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxycytosine (O2-pobdC), O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxythymidine (O2-pobdT) and O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O6-pobdG) which causes the G to T transversion and G to A transitions. 7-pobdG and O2-pobdC releases the nucleobases like 7-[4-(3-pyridyl)-4-oxobut-1-yl]-guanine and O2- [4-(3-pyridyl)-4-oxobut-1-yl]-cytosine creating an abasic site. Some of the pyridyloxobutyl DNA adducts are not stable and they undergo dealkylation to produce 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) [46, 47, t].
Fig.7. Role of NNK in forming adducts 
NNK in skin cancer
The mechanism of NNK in skin cancer is same as that of the oesophageal cancer.
There is no evidence for the association between the smoking and multiple myeloma [54, 55, 56, u].
XRCC1 is one of the genes which get involved in the BER pathways. BER is the main pathway which guards the DNA from the damages caused by UV, ionizing radiation, cellular metabolism, including the reactive oxygen species, methylation, deamination and hydroxylation. XRCC1 is used in the BER by interacting with the DNA repair proteins like PARP, DNA ligase III and DNA pol β. It is found to have eight nonsynonymous SNPs. Among which three of the polymorphism is found to be common and it includes the amino acid substitutions of Arg194 to Trp (C to T) of exon 6, Arg280 to His (G to A) of exon 9 and Arg399 to Gln (G to A)  of exon 10 [17, 22]. The Arg399 to Gln polymorphism is found in the BRCT-1 interaction domain of XRCC1 within the region of PARP and this polymorphism is related to the cancer risk [4, 17]. Variation in the Gln399 allele decreases the DNA repair capacity of XRCC1 which is due to the formation of the DNA adducts, high level of the sister chromatid exchange, increased RBC glycophorin A, p53 mutations and prolonged delay in the cell cycle [4, 16, 23]. The variations in the residue Arg194 and 280 is known to occur in the proliferating cell nuclear antigen binding region which contains polar Pro, Ser and Arg/Lys rich regions. The function of XRCC1 is altered by the transition of the positively charged amino acid Arg to the hydrophobic Trp within the conserved region. It was reported by Wang et al that the variations in the Trp194 allele had fewer belomycinor benzo[a]pyrene diol epoxides induced chromosomal breaks than that of the wild genotype. Polymorphisms at the codon 288 and 399 didn't have any association with the altered DNA levels and the G2 cell cycle delay.
Substitution of G28152 with A at codon 399 of exon 10 increases the risk of cancer. Lunn reported that the XRCC1 28152 polymorphism in codon 399 is related to the increased level of aflatoxin B1-DNA adducts and glycophorin A variants in the normal population [4, 16]. BER repairs the PAH-DNA adducts by metabolizing them by means of radical cation intermediates to electrophiles which binds to DNA and destabilizes the N-glycosyl bond by quick depurination or depyrimidation of the bases that are adducted .
Interaction between 1, 4-benzoquinone and XRCC1 inducing Leukemia
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1,4-benzoquinone which is a secondary metabolite of benzene formed the two-ring benzetheno exocyclic adducts with the bases C, A and G of the DNA which leads to the transition of G28152 to A and C26304 to T [44, 33, 34, 35, 37]. The transition of the gene is caused by the deficiency in the DNA repair [12, j].
Interaction between NNK and XRCC1 inducing oesophageal cancer
The activated from of NNK forms the diazohydroxide and the pyridyloxobutyl intermediate which forms the DNA adducts. The diazohydroxide formed by the methylation forms the adducts such as 7-methylguanine (7mG), O6-methylguanine (O6-mG) and O4-methylthymine (O4-mT) which causes the transition of G27466 to A. The pyridyloxobutyl intermediates formed by the pyridyloxobutylation reaction forms adduct with XRCC1 which includes 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (7-pobdG), O2- [4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxycytosine (O2-pobdC), O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxythymidine (O2-pobdT) and O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O6-pobdG) which causes the transversion of G28152 to T. 7-pobdG and O2-pobdC releases the nucleobases like 7-[4-(3-pyridyl)-4-oxobut-1-yl]-guanine and O2- [4-(3-pyridyl)-4-oxobut-1-yl]-cytosine creating an abasic site. Due to the formation of the adducts, the XRCC1 gets mutated and it does not get involved in the BER pathway which repairs the abasic sites created in the DNA [41, 42, 46, 47].
Interaction between NNK and XRCC1 induced skin cancer through follicular lymphoma 
Skin cancer is not directly caused by the carcinogens present in the tobacco smoke. Lymph that is present everywhere carries the carcinogen to various parts of the body. NNK is the carcinogen that causes the follicular lymphoma by forming the DNA adducts. The follicular lymphoma is metastasized to skin causing skin cancer [p, q, r, s].
In the case of follicular lymphoma, the procarcinogen NNK is activated by the CYP1A1 enzyme present in the liver. The activated NNK is converted to the pyridyloxobutylating intermediate which forms the 8-hydroxydeoxy- guanosine (8-OHdG) adduct with the DNA and causes the tranversion of G28152 to T .
Alterations found in Leukemia
XRCC1 plays a vital role in the BER pathway and it is also found to repair the single strand breaks in the DNA. The gene product of XRCC1 has the BRCA1 C-terminus (BRCT) domain which gets participated in the recognition of the damages in the DNA and its response. The polymorphism of the XRCC1 gene includes the substitution of Arg399 with Gln in exon 10 which is accompanied by the transition of G28152 to A and it also includes the replacement of Arg194 with Trp which is accompanied by the transition of C26304 to T. The codon 194 is found in the linker region which connects the domains that can interact with PARP and DNA polymerase β and the codon 399 is found in the BRCT domain which is functionally important. Polymorphism at the codon 399 increased the level of the damage and it has been finally concluded that the polymorphism of 399Gln had an increased risk in the light smokers where as it showed decreased risk in the heavy smokers [33, 34, 35, 37]. The increased level of the DNA damage caused by the smoke may lead to enhanced apoptosis during cell division and this can lead to the reduced risk of the cancer .
XRCC1 and XRCC3 alterations found in skin cancer
Tobacco smoking which includes the cigarette and the pipe smoking increases the risk of the cutaneous squamous cell carcinoma . When the human skin is exposed to the cigarette smoke, it creates an oxidative stress on the skin and the exposure increases the level of the hydroperoxide which has been derived from the cigarette smoke. It has various effects on the skin like wrinkling and also includes some of the disorders of the skin like impairment in the barrier function of the skin . But the free radical present in the smoke does not cause any alterations in the gene. The cancer is caused through the follicular lymphoma from where the inhaled carcinogens travel to the skin and causes the alteration in XRCC1 gene which includes the substitution of Arg399 with Gln accompanied by the G28152 to A transtition in exon 10 [12, 38, 49, 52]. The polymorphism of Arg399 shows an increased risk to the cancer. The polymorphism of XRCC1 which includes the substitution of Arg194 with Trp had an increased moderately increased risk and it includes the transition of C26304 to T .
Alterations found in oesophageal cancer
Oesophageal adenocarcinoma (EADC) is believed to arise from the Barett oesophagus (BE). BE is an acquired condition which is characterized by the replacement of the normal oesophageal epithelium with the metaplastic columnar cell-lined epithelium. The BE gets developed in to the EADC by the sequence of metaplasia- dysplasia-carcinoma and there is a link between the gastroesophageal reflux disease (GERD), BE and EADC as GERD is a risk factor BE . The codon 194 and 280 are found to be located between the binding regions of the DNA polymerase β and PARP whereas the codon 399 resides in the BRCT-1 domain region where the PARP can bind. It includes three types of polymorphism. First is the substitution of Arg 194 with Trp which is accompanied by the transition of C26304 to T in exon 6. Second polymorphism which includes the replacement of amino acid, Arg399 with Gln is accompanied by the transition of G28152 to T in exon 10. The final polymorphism with the change in the residue from Arg280 to His is accompanied by the transition of G27466 to A in exon 9. All the three polymorphisms showed an increased risk to the cancer [41, 42].