**1. Introduction**

524 DNA Repair

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The genetic material, DNA, which encodes genes needed for the production of essential proteins, is vulnerable to damage in a number of ways. Human DNA is assaulted on a daily basis by a variety of exogenous factors including UV light, cigarette smoke, dietary factors, and other carcinogens all of which can cause varying degrees of DNA damage and can lead to mutations. Similarly, endogenous factors such as undue DNA replication which can cause mismatches, hydrolysis leading to spontaneous DNA depurination, replication form collapse which can result in strand breaks, loss of bases because of spontaneous disintegration of chemical bonds, and DNA damage secondary to endogenous reactants such as alkyl groups, metal cations, and reactive oxygen species (ROS) which can induce base oxidation and DNA breaks also contribute to DNA damage (Branzei & Foiani, 2008; Capella et al., 2008)

When DNA is damaged, an intertwined network of surveillance mechanisms will act including


DNA damages are repaired by enzymes coded by one or more DNA repair pathways according to their structure, or their location in the cellular genome. DNA repair enzymes can be characterized as cellular proteins acting directly on damaged DNA in an attempt to restore the correct DNA sequence and structure. These relatively specialized enzymes appear to undertake the initial stages of recognition and repair of specific forms of DNA damage. Since there are various kinds of DNA damage, a variety of repair mechanisms are essential. Cells integrate DNA repair process with transcription and apoptosis through a network known as the DNA damage response (DDR) which is orchestrated by the checkpoint proteins.

Low Penetrance Genetic Variations in DNA Repair Genes and Cancer Susceptibility 527

LiFraumeni Syndrome). But these genes affect only a small portion of cancer cases and a

Loss of function mutations in a significant number of DNA damage response genes predispose to a variety of familial cancers (Spry et al., 2007). There are several examples such as mutations in BRCA1 and BRCA2 belonging to homologous recombination pathways predispose to breast and ovarian cancer (Bertwistle & Ashworth, 2000). So also, mutations in other double strand break repair genes such as ATM predispose to the familial tumorigenic condition ataxia telangiectasia (Lavin & Shiloh 1996) and breast cancer (Renwick et al., 2006). Mutations in NBSI have been reported to predispose to Nijwegen breakage syndrome (Matsuura et al., 2004). Somatic mutations in another DSB repair gebe, ATR, correlate with sporadic microsatellite (MSI) positive stomach cancer (Menoyo et al., 2001). PALB2 gene, which encodes a BRCA2 indicating protein, has also been identified as a breast cancer susceptibility gene (Rahman et al., 2007). Mutations in a group of DNA mismatch repair (MMR) gene predispose to hereditary non-poplyposis colorectal cancer and other cancers in the extra colonic sites in Lynch syndrome (Jacob & Praz, 2002). Biallelic germline mutations of the base excision repair gene MUTYH have been identified in patients with autosomal recessive form of hereditary multiple colorectal adenoma and carcinoma (Jones et al., 2002). Defect in the nucleotide excision repair pathway genes predispose to xeroderma pimentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD), which are all

In contrast, in the remaining major portion of sporadic cases, genetic variations in the form of low to moderate penetrance alleles may predispose individuals to cancer in combination with environmental factors and thus affect a large segment of the population. Low penetrance genes, also referred to as modifier genes, are genes in which subtle sequence variants may be associated with a small to moderate increased relative risk for sporadic

Genetic variations seen in human genome includes insertion/deletion of one or more nucleotides (indels) the copy number variations (CNNs) that can involve DNA sequences of a few kilobases up to millions of bases and single nucleotide polymorphisms (SNPs) which are the substitution of a single nucleotide along the DNA. With an estimated number of more than 10 million to be present in the human genome, SNPs are the most common form

Variations in several classes of low penetrance genes known as Single nucleotide polymorphism (SNPs) are very common in the population. SNPs are DNA sequence variations that occur when a single nucleotide (A, T, C, or G) in the genome sequence is altered. For a variation to be considered as SNP, it must be present in at least 1% of the population. SNPs are relatively common in the population and as such may be associated with a much higher attributable risk in the population as a whole than the rare high penetrance genes. Therefore, variants in low penetrance genes could explain a greater proportion of sporadic cancers than the high penetrance genes. SNPs acting together with environmental factors are well documented candidates for cancer susceptibility. Even though, SNPs in these low penetrance genes have only small effect when considered singly, they may produce a high risk profile when acting together with other shared genetic variants and environmental factors (Gary et al., 1999). On the basis of biological plausibility,

**4. Single Nucleotide Polymorohisms (SNPs) in low penetrance genes** 

small percent age of the population.

autosomal recessive syndromes (Leibeling et al., 2006).

of genetic variation (Miller et al., 2005).

cancers.

### **2. DNA repair pathways**

Damages in DNA are repaired by various DNA repair genes belonging to distinct pathways. Each pathway is recognized for efficient repair of specific types of DNA damage. To date, more than 150 human DNA repair genes have been identified, which can be categorized into at least 5 distinct pathways: Base Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Double Strand Break Repair (DSBR), and Transcription Coupled Repair (TCR) (Wood et al., 2005). The Base Excision Repair Pathway operates on small lesions such as oxidized or reduced bases, fragmented or nonbulky adduct, and adducts produced by methylating agents. The Nucleotide Excision repair (NER) pathway repairs bulky lesions such as pyramidine dimmers, other products of phytochemical reactions, large chemical adducts and DNA crosslinks. For Double Strand Break Repair (DSBR), at least two pathways exist: homologous recombination and non homologous end joining. Replication errors such as base-base or insert-deletion mismatches caused by the DNA polymerase are repaired by Mismatch Repair (MMR) pathway genes. Finally, the suicide enzyme methylguanine-DNA, methyl transferase, is an additional category of DNA repair pathway that directly removes the alkylated bases.

The repair gene products operate in a co-ordinated fashion to form repair pathways that control restitution of specific types of DNA damage. Repair pathways are further coordinated with other metabolic processes, such as cell cycle control, to optimize the prospects of successful repair. During the cell cycle, checkpoint mechanisms ensure that a cell's DNA is intact before permitting DNA replication and cell division to occur. Failures in these checkpoints can lead to an accumulation of damage, which in turn leads to mutations.

Repair of damaged DNA is of paramount importance and is essential to prevent loss of or in correct transmission of genetic information, to prevent genetic damage from propagating and accumulating, to maintain genome integrity and stability of cells, and also to prevent mutations The failure of the cell to adequately repair the acquired damage and to undergo apoptosis may lead to further errors which can cause developmental abnormalities and neoplastic transformation of the cell and finally to carcinogenesis.

#### **3. Genetic susceptibility to cancer - High and low penetrance DNA repair genes**

Genetic susceptibility to cancer result from variations in the genetic code that alter either protein expression, function or localization. Susceptibility to cancer is determined by two types of genes – high penetrance genes and low penetrance genes. High penetrance genes are genes with allelic variants that confer a high degree of risk to the individual. Relatively few individuals in the population carry risk –increasing genotypes at these loci. The proportion of cancer in the population that may be explained by these genotypes will be low. Therefore the population attributable risk also will be low. But high penetrance genes have a large magnitude of effects on cancer risk and usually follow a mendelian autosomal domiant pattern of inheritance and involve multiple cancer sites that form a cancer syndrome. High penetrance genes with an attendant high likelihood of causing cancer, account for only a small proportion of cancer cases. In humans, high penetrance DNA repair genes that cause family or hereditary cancer syndromes can have substantial impact in affected families (eg: BRCA1 and BRCA2 genes in hereditary breast cancer, DNA Mismatch Repair (MMR) genes in Hereditary Non Polyposis Colorectal Cancer (HNPCC), p53 in

Damages in DNA are repaired by various DNA repair genes belonging to distinct pathways. Each pathway is recognized for efficient repair of specific types of DNA damage. To date, more than 150 human DNA repair genes have been identified, which can be categorized into at least 5 distinct pathways: Base Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Double Strand Break Repair (DSBR), and Transcription Coupled Repair (TCR) (Wood et al., 2005). The Base Excision Repair Pathway operates on small lesions such as oxidized or reduced bases, fragmented or nonbulky adduct, and adducts produced by methylating agents. The Nucleotide Excision repair (NER) pathway repairs bulky lesions such as pyramidine dimmers, other products of phytochemical reactions, large chemical adducts and DNA crosslinks. For Double Strand Break Repair (DSBR), at least two pathways exist: homologous recombination and non homologous end joining. Replication errors such as base-base or insert-deletion mismatches caused by the DNA polymerase are repaired by Mismatch Repair (MMR) pathway genes. Finally, the suicide enzyme methylguanine-DNA, methyl transferase, is an additional category of DNA repair pathway that

The repair gene products operate in a co-ordinated fashion to form repair pathways that control restitution of specific types of DNA damage. Repair pathways are further coordinated with other metabolic processes, such as cell cycle control, to optimize the prospects of successful repair. During the cell cycle, checkpoint mechanisms ensure that a cell's DNA is intact before permitting DNA replication and cell division to occur. Failures in these checkpoints can lead to an accumulation of damage, which in turn leads to mutations. Repair of damaged DNA is of paramount importance and is essential to prevent loss of or in correct transmission of genetic information, to prevent genetic damage from propagating and accumulating, to maintain genome integrity and stability of cells, and also to prevent mutations The failure of the cell to adequately repair the acquired damage and to undergo apoptosis may lead to further errors which can cause developmental abnormalities and

neoplastic transformation of the cell and finally to carcinogenesis.

**3. Genetic susceptibility to cancer - High and low penetrance DNA** 

Genetic susceptibility to cancer result from variations in the genetic code that alter either protein expression, function or localization. Susceptibility to cancer is determined by two types of genes – high penetrance genes and low penetrance genes. High penetrance genes are genes with allelic variants that confer a high degree of risk to the individual. Relatively few individuals in the population carry risk –increasing genotypes at these loci. The proportion of cancer in the population that may be explained by these genotypes will be low. Therefore the population attributable risk also will be low. But high penetrance genes have a large magnitude of effects on cancer risk and usually follow a mendelian autosomal domiant pattern of inheritance and involve multiple cancer sites that form a cancer syndrome. High penetrance genes with an attendant high likelihood of causing cancer, account for only a small proportion of cancer cases. In humans, high penetrance DNA repair genes that cause family or hereditary cancer syndromes can have substantial impact in affected families (eg: BRCA1 and BRCA2 genes in hereditary breast cancer, DNA Mismatch Repair (MMR) genes in Hereditary Non Polyposis Colorectal Cancer (HNPCC), p53 in

**2. DNA repair pathways** 

directly removes the alkylated bases.

**repair genes** 

LiFraumeni Syndrome). But these genes affect only a small portion of cancer cases and a small percent age of the population.

Loss of function mutations in a significant number of DNA damage response genes predispose to a variety of familial cancers (Spry et al., 2007). There are several examples such as mutations in BRCA1 and BRCA2 belonging to homologous recombination pathways predispose to breast and ovarian cancer (Bertwistle & Ashworth, 2000). So also, mutations in other double strand break repair genes such as ATM predispose to the familial tumorigenic condition ataxia telangiectasia (Lavin & Shiloh 1996) and breast cancer (Renwick et al., 2006). Mutations in NBSI have been reported to predispose to Nijwegen breakage syndrome (Matsuura et al., 2004). Somatic mutations in another DSB repair gebe, ATR, correlate with sporadic microsatellite (MSI) positive stomach cancer (Menoyo et al., 2001). PALB2 gene, which encodes a BRCA2 indicating protein, has also been identified as a breast cancer susceptibility gene (Rahman et al., 2007). Mutations in a group of DNA mismatch repair (MMR) gene predispose to hereditary non-poplyposis colorectal cancer and other cancers in the extra colonic sites in Lynch syndrome (Jacob & Praz, 2002). Biallelic germline mutations of the base excision repair gene MUTYH have been identified in patients with autosomal recessive form of hereditary multiple colorectal adenoma and carcinoma (Jones et al., 2002). Defect in the nucleotide excision repair pathway genes predispose to xeroderma pimentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD), which are all autosomal recessive syndromes (Leibeling et al., 2006).

In contrast, in the remaining major portion of sporadic cases, genetic variations in the form of low to moderate penetrance alleles may predispose individuals to cancer in combination with environmental factors and thus affect a large segment of the population. Low penetrance genes, also referred to as modifier genes, are genes in which subtle sequence variants may be associated with a small to moderate increased relative risk for sporadic cancers.
