1. Introduction
DNA repair is a process vital to the cell since the genetic material is the target of a multitude of daily attacks. Cells have evolved into possessing distinct but simultaneously intercalating ways of dealing with repair of DNA lesions. These repair pathways may include practices dealing with single strand damage (Base Excision Repair, Nucleotide Excision Repair, Mismatch Repair) or with double strand damage (Non-homologous End Joining and Homologous Recombination) as well as Direct Reversal Repair and Translesion Synthesis. The present chapter deals with one of these pathways (Base Excision Repair), which rectifies damage at the point of the single nucleotide.
2. Overview of base excision repair
Small non-helix distorting DNA alterations are very common in living organisms and they are due both to exogenous and endogenous sources. Endogenous damage can be summarised into the following categories: a) misincorporation of uracil in the genome or spontaneous deamination of cytosine (Sung and Demple, 2006) b) hydrolysis of all four bases or oxidation by reactive oxygen species (ROS), hormones, reactive nitrogen species, heme precursors and amino acids (Nilsen and Krokan, 2001; Wood et al., 2001) c) alkylation of purines and pyrimidines by lipid end-products (Sung and Demple, 2000) or other parameters (e.g. S-adenyl-methionine). Spontaneous abasic sites are also common lesions and 10000 purines are detached from DNA per human genome per day (Wilson and Kunkel, 2000; Nilsen and Krokan, 2001). Besides all these endogenous reactions, exogenous agents as xenobiotics and radiation are also able to cause similar damage. All these small, point lesions are rectified by Base Excision Repair (BER) (Krokan et al., 2000; Cabelof et al., 2002). BER was discovered by Tomas Lindahl in 1974 (Krokan et al., 2000), it is a tightly conserved pathway from bacteria to mammals (Izumi et al., 2003; Didzaroglu, 2005) and it must be preserved in a highly coordinated way to be effective (Moustacchi, 2000; Allinson et al., 2004).
BER is initiated by the cleaving of the damaged base by a specialized enzyme: a DNA
The AP site created (as well as the SSB) must be quickly processed further since they are highly cytotoxic (Allinson et al., 2004) and mutagenic (Nilsen and Krokan, 2001). This is done by an AP endonuclease (APE1 for mammalian organisms) resulting in the formation of a 3΄-hydroxyl end (3΄OH) and a 5΄ abasic sugar phosphate end (5΄dRP) (Memisoglu and Samson, 2000). AP endonuclease APE1 is also involved in the “trimming” of the blocked 3΄ end created by bifunctional glycosylases (Mitra et al., 2001; Cabelof et al., 2002; Izumi et al., 2003). However some researchers argue that the phosphatase activity of APE1 is low and that polynucleotide kinase (PNK) is the only enzyme that cleaves successfully the products of βδ-elimination (Mitra et al., 2002; Wiederhold et al., 2004).
The formation of SSB by APE1 is a critical point in the BER process since two sub-pathways may follow: the short-patch or the long-patch pathway (Christmann et al., 2003; Sung and Demple, 2006). The short patch may be initiated by
No matter what the underlying reason for differentiation is, the two sub-pathways are substantially different. In the short-patch polymerase β attaches a single nucleotide to the trimmed 3΄OH end, displacing the dRP at the 5΄end (Wilson and Thompson, 1997; Schärer and Jiricny, 2001) and it also cleaves 5΄dRP by its intrinsic lyase activity through a covalent Schiff intermediate (Sung and Demple, 2006). Ligase III/XRCC1 seals the gap and DNA integrity is restored (Wilson and Thompson, 1997; Cabelof et al., 2002). Polymerase β does not have proofreading abilities and sometimes it incorporates an incorrect nucleotide which is subsequently re-excised by APE1 (Noble, 2002). In the long-patch, polymerase β or polymerase δ/ε with the proliferating cell nuclear antigen (PCNA), add a few more nucleotides at the 3΄OH end (Christmann et al., 2003). The number of extra nucleotides is according to researchers up to six (Schärer and Jiricny, 2001), up to ten (Christmann et al., 2003) or up to thirteen (Suttler et al., 2003). This action creates a flap at the 5΄dRP end. This flap is then excised by flap endonuclease (FEN1) and afterwards PCNA/ligase I seals the gap (Christmann et al., 2003). A representation of BER pathways is depicted in Figure 1.
3. Common polymorphisms in BER and cancer risk
Given the crucial role of BER in DNA repair, it is expected that polymorphisms which alter enzyme activity may be linked with increased cancer risk.
The substitution of serine by cysteine in codon 326 (Ser326Cys) in OGG1
On the contrary, mutations in the MYH gene (see also subchapter 4) have been proven without doubt to be able to cause an autosomal recessive form of familial adenomatous polyposis (Lindor, 2009). Individuals with biallelic inherited mutations of the MYH gene run a high risk of colorectal cancer that approaches 100% (Dolwani et al., 2007). Transversion mutations in MYH disrupt the normal base excision repair of adenines misincorporated opposite 7,8-dihydro-8-oxoguanine, a prevalent and stable product of oxidative damage to DNA, leading to hereditary colorectal neoplasms (Sampson et al, 2005). Patients with MYH-associated polyposis (MAP) present with clinical features similar to classic FAP (familial adenomatous polyposis). Patients typically present between the ages of 40–60 years with a variable number of colorectal adenomatous polyps, however, MYH mutation carriers do not usually present with multiple polyps before the age of 30 years (Kastrinos and Syngal, 2007).
Given the critical role of APE1 in BER a total of 18 polymorphisms in APE1 gene have been reported. The most extensively studied is the Asp148Glu; A meta-analysis of 12432 cases showed an increased risk of cancers, especially of colorectal cancer for this allele. Functional studies have shown that this variant may have altered endonuclease and DNA-binding activity and reduced ability to interact with other BER proteins (Gu et al., 2009) in order to form critical complexes for nucleotide excision/incorporation during the rectifying process. Besides its endonuclease activity, APE1 has been shown to stimulate the DNA binding activity of numerous transcription factors that are involved in cancer promotion and progression such as Fos, Jun, nuclear factor-κB and p53, thus is actively involved in redox regulation of oncoproteins (Kelley et al., 2010).
The XRCC1 protein plays a major role in facilitating the repair of single-strand breaks in mammalian cells, via an ability to interact with multiple enzymatic components of repair reactions (Caldecott, 2003). In BER, XRCC1 acts as a scaffold for DNA ligase III, polymerases and PAPR. Some of the most common XRCC1 polymorphisms are Arg194Trp, Arg280His and Arg399Gln (Xue et al., 2011). A meta-analysis of 40 studies regarding these three polymorphisms and breast cancer showed a recessive effect of Arg280His and Arg399Gln variants in Asians only (Li et al., 2009). However, no increase in gastric cancer risk for Arg194Trp, Arg280His and Arg399Gln has been noted (Geng et al., 2008; Xue et al., 2011). According to other studies, the Arg194Trp variant contributes to a reduced risk of various types of cancer (Goode et al., 2002; Hu et al., 2005). Indeed, the XRCC1 Arg194Trp and Arg280His variants were each associated with a reduced risk of lung cancer compared with common allele homozygotes (Hung et al., 2005). These last results are somewhat surprising since a common perception is that a change in amino-acid structure would be deleterious to function and would result in an increased risk of cancer. In the specific case of XRCC1, it is possible that a change to tryptophan would cause a transition from the positively charged arginine of the wild type to a hydrophobic tryptophan, which could positively affect binding to DNA and increase efficiency (Ladiges, 2006).
PCNA, another important component for BER polymerases scaffolding is also characterised as “the ringmaster of the genome”. It interacts with p53-controlled proteins Gadd45, MyD118, CR6 and p21, in the process of deciding cell fate: proliferation, repair or apoptosis (Paunesku et al., 2001). A novel form of PCNA has been described in malignant breast cells. This unique form is not the result of a genetic alteration, as demonstrated by DNA sequence analysis but it is the product of post-translational modification. This example shows the diverse and multifaceted ways that BER enzyme variations may affect cancer frequency (Bechtel et al., 1988).
4. Specific BER N-glycosylases implicated in oxidised base removal
4.1. Prokaryotic organisms (E.coli )
Fpg (MutM): Formamidopyrimidine glycosylase (Fpg) is a glycosylase which excises 8-oxo-deoxyguanosine (8-oxo-dG) from 8-oxo-dG: C pairs (Beckman and Ames, 1997; Gros et al., 2002; Russo et al., 2006), but not from 8-oxo-dG: A mispairs because that would lead to a stable G-T transition (Wang et al., 1998). One of the most extensively studied glycosylases, Fpg has been also found in
Nei (endo VII): Nei exhibits an overlapping substrate-specificity with Fpg. It comprises 263 amino acids and a C-terminal Zn finger motif (Gros et al., 2002; Rosenquist et al., 2003).
MutT: MutT is a GTPase which sanitises nucleotide pools from 8-oxo-GTP by hydrolysing it to monophosphate, thus preventing its misincorporation in DNA (Beckman and Ames, 1997; Fortini et al., 1999). MutT deficient strains exhibit a strong mutator phenotype (Fortini et al., 1999).
MutY: MutY excises A which is wrongly incorporated opposite 8-oxo-dG (Beckman and Ames, 1997; Vidal et al., 2001). MutY is a 39 kDa protein which can also excise A opposite to G, C and 8-oxo-dA (Le Page et al., 1999; Gros et al., 2002). Fpg/MutY double null strains exhibit a strong mutator phenotype (Wang et al., 1998; Russo et al., 2006).
Nth: Nth also excises Fpg substrates and it has a strong activity against thymine glycol and other oxidised pyrimidines (Gros et al., 2002; Izumi et al., 2003; Rosenquist et al., 2003). Nth possesses a β-lyase activity besides its
The triad MutT, MutY and MutM (Fpg) comprise the so called GO system which suppresses effectively Guanine Oxidation via the concerted actions of sanitising of the nucleotide pool, excising misincorporated A and excising 8-oxo-dG from duplex DNA respectively (Beckman and Ames, 1997).
4.2. Eykaryotic organisms (mammals)
OGG1: hOGG1 is the functional analogue of Fpg in humans. Besides 8-oxo-dG, OGG1 has activity against Fapy (Nohmi et al., 2005) and very weak activity against 4,6-diamino-5-formamidopyrimidine (FapyA) (Wallace, 2002). The mammalian OGG1 contains a helix-hairpin-helix motif (HhH) with an Asp-activated Lys residue as an active site. The residue forms a Schiff base with the substrate and subsequently creates an AP site (Izumi et al., 2003). OGG1 is a bifunctional glycosylase, however it acts as a monofunctional
NEIL: 3 human and 3 mouse homologues of the bacterial Nei have been cloned, namely NEIL1, NEIL2 and NEIL3. They contain a helix-two turn-helix motif and NEIL 2 and 3 may also contain Zn finger motifs (Rosenquist et al., 2003). NEIL1 and NEIL2 perform a βδ elimination on their substrate with a 3΄ and a 5΄ phosphate strand as end products (Izumi et al., 2003). NEIL excises thymine glycol (TG), FapyG and FapyA but shows only nominal activity against 8-oxo-dG (Rosenquist et al., 2003). According to other researchers NEIL activity against 8-oxo-dG is significant and the tissue-specific high expression of NEIL3 may be a back up mechanism for removal of oxidised guanine (Slupphaug et al., 2003).
MTH1: the mammalian homologue of MutT is MTH1. MTH1 sanitises the nucleotide pool from 8-oxo-GTP and it also degrades 2OH-dATP and 2OH-ATP (Slupphaug et al., 2003; Nohmi et al., 2005).
MYH: the mammalian homologue of MutY is MYH. MYH removes A from 8-oxo-dG:A mispairs (Nagashima et al., 1997; Fortini et al., 1999). It also recognises A:G and A:C mispairs (Fortini et al., 1999; Izumi et al., 2003). It is mainly a monofunctional glycosylase with a weak AP lyase activity (Russo et al., 2006). Important variants of MYH were found in siblings afflicted by multiple colon adenoma and carcinoma and further studies proved its role in colorectal adenoma and carcinoma predisposition (Gros et al., 2002; Nohmi et al., 2005). Double mutants mice for MYH and OGG1 had increased tumours in lung, small intestine and ovaries (Russo et al., 2006). The unique action of MYH does not seem to have any back up from other glycosylases, which explain the importance of its mutations (Izumi et al., 2003).
NTH1: The mammalian homologue of nth is NTH1. NTH1 has similar substrate specificity with nth (Gros et al., 2002). It possesses both an
OGG2: the novel glycosylase OGG2 has been found in human (Wang et al., 1998; Bohr and Dianov, 1999) and yeast (Nash et al., 1996) cells. OGG2 probably excises wrongly incorporated 8-oxo-dG opposite A, in a nascent strand (Izumi et al., 2003).
The triad MTH1, MYH and OGG1 together with other accessory proteins like OGG2 and NEIL comprise the mammalian GO system which suppresses effectively Guanine Oxidation. A representation of the GO system is given in Figure 2.
5. Specific BER N-glycosylases implicated in alkylated base removal
It has been estimated that 20,000 DNA lesions are produced per cell per day but the contribution of alkylation damage is not well established (Drabløs et al., 2004). However alkylation damage occurs frequently as part of the normal metabolism of the cell. It has been shown that the methyl donor
5.1. Prokaryotic organisms (E.coli )
Tag: The bacterial Tag excises 3meA and 3meG from dsDNA only (Bjeeland and Seeberg, 1996) and it is not inducible (Seeberg et al., 1995).
deficient organisms (Xiao and Samson, 1993). These data suggest that the expression of Tag should be carefully controlled for achievement of optimal activity.
AlkA: The bacterial AlkA excises 3meA, 7meA, 7meG,
5.2. Eukaryotic organisms (mammals)
AAG (MPG, ANPG): The mammalian AAG shares the same broad specificity with the bacterial AlkA. It also removes intact guanines at very low frequencies but it cannot remove
As already mentioned. AAG is able to rectify exocyclic etheno adducts like εdA, 3,N4-ethenodeoxycytidine (εdC), 1,
6. Conclusion
Base Excision Repair pathway is a tightly conserved pathway, from prokaryotic organism to higher mammals. At the same time it is an adapting and flexible mechanism, which covers repair of a variety of small DNA lesions as evidenced by its diverse
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