Base excision repair

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Basic steps of base excision repair BER basic pathway.svg
Basic steps of base excision repair

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch (where a single nucleotide is replaced) or long-patch BER (where 2–10 new nucleotides are synthesized). [1]

Contents

Lesions processed by BER

8-oxoguanine forms a Hoogsteen base pair with adenine 8-oxoG forming Hoogsten base pair with dA.svg
8-oxoguanine forms a Hoogsteen base pair with adenine

Single bases in DNA can be chemically damaged by a variety of mechanisms, the most common ones being deamination, oxidation, and alkylation. These modifications can affect the ability of the base to hydrogen-bond, resulting in incorrect base-pairing, and, as a consequence, mutations in the DNA. For example, incorporation of adenine across from 8-oxoguanine (right) during DNA replication causes a G:C base pair to be mutated to T:A. Other examples of base lesions repaired by BER include:

In addition to base lesions, the downstream steps of BER are also utilized to repair single-strand breaks.

The choice between long-patch and short-patch repair

The choice between short- and long-patch repair is currently under investigation. Various factors are thought to influence this decision, including the type of lesion, the cell cycle stage, and whether the cell is terminally differentiated or actively dividing. [3] Some lesions, such as oxidized or reduced AP sites, are resistant to pol β lyase activity and, therefore, must be processed by long-patch BER.

Pathway preference may differ between organisms, as well. While human cells utilize both short- and long-patch BER, the yeast Saccharomyces cerevisiae was long thought to lack a short-patch pathway because it does not have homologs of several mammalian short-patch proteins, including pol β, DNA ligase III, XRCC1, and the kinase domain of PNKP. The recent discovery that the poly-A polymerase Trf4 possesses 5' dRP lyase activity has challenged this view. [4]

Proteins involved in base excision repair

DNA glycosylases

Uracil DNA glycosylase flips a uracil residue out of the duplex, shown in yellow. Uracil base glycosidase.jpg
Uracil DNA glycosylase flips a uracil residue out of the duplex, shown in yellow.

DNA glycosylases are responsible for initial recognition of the lesion. They flip the damaged base out of the double helix, as pictured, and cleave the N-glycosidic bond of the damaged base, leaving an AP site. There are two categories of glycosylases: monofunctional and bifunctional. Monofunctional glycosylases have only glycosylase activity, whereas bifunctional glycosylases also possess AP lyase activity. Therefore, bifunctional glycosylases can convert a base lesion into a single-strand break without the need for an AP endonuclease. β-Elimination of an AP site by a glycosylase-lyase yields a 3' α,β-unsaturated aldehyde adjacent to a 5' phosphate, which differs from the AP endonuclease cleavage product. [5] Some glycosylase-lyases can further perform δ-elimination, which converts the 3' aldehyde to a 3' phosphate. A wide variety of glycosylases have evolved to recognize different damaged bases. Examples of DNA glycosylases include Ogg1, which recognizes 8-oxoguanine, MPG, which recognizes 3-methyladenine, and UNG, which removes uracil from DNA.

AP endonucleases

The AP endonucleases cleave an AP site to yield a 3' hydroxyl adjacent to a 5' deoxyribosephosphate (dRP). AP endonucleases are divided into two families based on their homology to the ancestral bacterial AP endonucleases endonuclease IV and exonuclease III. [6] Many eukaryotes have members of both families, including the yeast Saccharomyces cerevisiae, in which Apn1 is the EndoIV homolog and Apn2 is related to ExoIII. In humans, two AP endonucleases, APE1 and APE2, have been identified. [7] It is a member of the ExoIII family.


End processing enzymes

In order for ligation to occur, a DNA strand break must have a hydroxyl on its 3' end and a phosphate on its 5' end. In humans, polynucleotide kinase-phosphatase (PNKP) promotes formation of these ends during BER. This protein has a kinase domain, which phosphorylates 5' hydroxyl ends, and a phosphatase domain, which removes phosphates from 3' ends. Together, these activities ready single-strand breaks with damaged termini for ligation. The AP endonucleases also participate in 3' end processing. Besides opening AP sites, they possess 3' phosphodiesterase activity and can remove a variety of 3' lesions including phosphates, phosphoglycolates, and aldehydes. 3'-Processing must occur before DNA synthesis can initiate because DNA polymerases require a 3' hydroxyl to extend from.

DNA polymerases

Pol β is the main human polymerase that catalyzes short-patch BER, with pol λ able to compensate in its absence. [8] These polymerases are members of the Pol X family and typically insert only a single nucleotide. In addition to polymerase activity, these enzymes have a lyase domain that removes the 5' dRP left behind by AP endonuclease cleavage. During long-patch BER, DNA synthesis is thought to be mediated by pol δ and pol ε along with the processivity factor PCNA, the same polymerases that carry out DNA replication. These polymerases perform displacing synthesis, meaning that the downstream 5' DNA end is "displaced" to form a flap (see diagram above). Pol β can also perform long-patch displacing synthesis and can, therefore, participate in either BER pathway. [9] Long-patch synthesis typically inserts 2-10 new nucleotides.

Flap endonuclease

FEN1 removes the 5' flap generated during long patch BER. This endonuclease shows a strong preference for a long 5' flap adjacent to a 1-nt 3' flap. [10] The yeast homolog of FEN1 is RAD27. In addition to its role in long-patch BER, FEN1 cleaves flaps with a similar structure during Okazaki fragment processing, an important step in lagging strand DNA replication.

DNA ligase

DNA ligase III along with its cofactor XRCC1 catalyzes the nick-sealing step in short-patch BER in humans. [11] [12] DNA ligase I ligates the break in long-patch BER. [13]

Defects in a variety of DNA repair pathways lead to cancer predisposition, and BER appears to follow this pattern. Deletion mutations in BER genes have shown to result in a higher mutation rate in a variety of organisms, implying that loss of BER could contribute to the development of cancer. Indeed, somatic mutations in Pol β have been found in 30% of human cancers, and some of these mutations lead to transformation when expressed in mouse cells. [14] Mutations in the DNA glycosylase MYH are also known to increase susceptibility to colon cancer. [15]

Epigenetic deficiencies in cancers

Epigenetic alterations (epimutations) in base excision repair genes have only recently begun to be evaluated in a few cancers, compared to the numerous previous studies of epimutations in genes acting in other DNA repair pathways (such as MLH1 in mismatch repair and MGMT in direct reversal).[ citation needed ] Some examples of epimutations in base excision repair genes that occur in cancers are summarized below.

MBD4

Hydrolysis of cytosine to uracil DesaminierungCtoU.png
Hydrolysis of cytosine to uracil

MBD4 (methyl-CpG-binding domain protein 4) is a glycosylase employed in an initial step of base excision repair. MBD4 protein binds preferentially to fully methylated CpG sites and to the altered DNA bases at those sites. These altered bases arise from the frequent hydrolysis of cytosine to uracil (see image) and hydrolysis of 5-methylcytosine to thymine, producing G:U and G:T base pairs. [16] If the improper uracils or thymines in these base pairs are not removed before DNA replication, they will cause transition mutations. MBD4 specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites. [17] This is an important repair function since about 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of G:C to A:T transitions. [17] [18] These transitions comprise the most frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites. [17] Thus, a decrease in expression of MBD4 could cause an increase in carcinogenic mutations.

MBD4 expression is reduced in almost all colorectal neoplasms due to methylation of the promoter region of MBD4. [19] Also MBD4 is deficient due to mutation in about 4% of colorectal cancers. [20]

A majority of histologically normal fields surrounding neoplastic growths (adenomas and colon cancers) in the colon also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. [19] This finding suggests that epigenetic silencing of MBD4 is an early step in colorectal carcinogenesis.

In a Chinese population that was evaluated, the MBD4 Glu346Lys polymorphism was associated with about a 50% reduced risk of cervical cancer, suggesting that alterations in MBD4 may be important in cancer. [21]

NEIL1

NEIL1 recognizes (targets) and removes certain oxidatively-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol. [22] The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing lesions from single-stranded DNA as well as from bubble and forked DNA structures. A deficiency in NEIL1 causes increased mutagenesis at the site of an 8-oxo-Gua:C pair, with most mutations being G:C to T:A transversions. [23]

A study in 2004 found that 46% of primary gastric cancers had reduced expression of NEIL1 mRNA, though the mechanism of reduction was not known. [24] This study also found that 4% of gastric cancers had mutations in NEIL1. The authors suggested that low NEIL1 activity arising from reduced expression and/or mutation in NEIL1 was often involved in gastric carcinogenesis.

A screen of 145 DNA repair genes for aberrant promoter methylation was performed on head and neck squamous cell carcinoma (HNSCC) tissues from 20 patients and from head and neck mucosa samples from 5 non-cancer patients. [25] This screen showed that NEIL1, with substantially increased hypermethylation, had the most significantly different frequency of methylation. Furthermore, the hypermethylation corresponded to a decrease in NEIL1 mRNA expression. Further work with 135 tumor and 38 normal tissues also showed that 71% of HNSCC tissue samples had elevated NEIL1 promoter methylation. [25]

When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors, 42% were hypermethylated in the NEIL1 promoter region. [26] This was the most frequent DNA repair abnormality found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be hypermethylated in their promoter regions in colorectal cancer. [27]

Demethylation of 5-Methylcytosine (5mC) in DNA. As reviewed in 2018, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, TET3) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt). Demethylation of 5-methylcytosine.svg
Demethylation of 5-Methylcytosine (5mC) in DNA. As reviewed in 2018, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, TET3) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt).

Active DNA methylation and demethylation is required for the cognition process of memory formation and maintenance. [29] In rats, contextual fear conditioning can trigger life-long memory for the event with a single trial, and methylation changes appear to be correlated with triggering particularly long-lived memories. [29] With contextual fear conditioning, after 24 hours, DNA isolated from the rat brain hippocampus region had 2097 differentially methylated genes, with a proportion being demethylated. [29] As reviewed by Bayraktar and Kreutz, [28] DNA demethylation is dependent on base excision repair (see figure).

Physical exercise has well established beneficial effects on learning and memory (see Neurobiological effects of physical exercise). BDNF is a particularly important regulator of learning and memory. [30] As reviewed by Fernandes et al., [31] in rats, exercise enhances the hippocampus expression of the gene Bdnf , which has an essential role in memory formation. Enhanced expression of Bdnf occurs through demethylation of its CpG island promoter at exon IV [31] and demethylation depends on base excision repair (see figure). [28]

Decline in BER with age

The activity of the DNA glycosylase that removes methylated bases in human leukocytes declines with age. [32] The reduction in the excision of methylated bases from DNA suggests an age-dependent decline in 3-methyladenine DNA glycosylase, a BER enzyme responsible for removing alkylated bases. [32]

Young rats (4- to 5 months old), but not old rats (24- to 28 months old), have the ability to induce DNA polymerase beta and AP endonuclease in response to oxidative damage. [33]

See also

Related Research Articles

Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

<span class="mw-page-title-main">Nucleotide excision repair</span> DNA repair mechanism

Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals, radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). While the BER pathway can recognize specific non-bulky lesions in DNA, it can correct only damaged bases that are removed by specific glycosylases. Similarly, the MMR pathway only targets mismatched Watson-Crick base pairs.

<span class="mw-page-title-main">AP site</span> Biochemical site of damaged DNA or RNA

In biochemistry and molecular genetics, an AP site, also known as an abasic site, is a location in DNA that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage. It has been estimated that under physiological conditions 10,000 apurinic sites and 500 apyrimidinic may be generated in a cell daily.

<span class="mw-page-title-main">MUTYH</span> Protein-coding gene in the species Homo sapiens

MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

<span class="mw-page-title-main">Werner syndrome helicase</span> Protein-coding gene in the species Homo sapiens

Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division. Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

<span class="mw-page-title-main">APEX1</span> Protein-coding gene in the species Homo sapiens

DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the APEX1 gene.

<span class="mw-page-title-main">LIG1</span> Protein-coding gene in the species Homo sapiens

DNA ligase 1 is an enzyme that in humans is encoded by the LIG1 gene. DNA ligase I is the only known eukaryotic DNA ligase involved in both DNA replication and repair, making it the most studied of the ligases.

The enzyme DNA-(apurinic or apyrimidinic site) lyase, also referred to as DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase or DNA AP lyase catalyzes the cleavage of the C-O-P bond 3' from the apurinic or apyrimidinic site in DNA via β-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. In the 1970s, this class of enzyme was found to repair at apurinic or apyrimidinic DNA sites in E. coli and in mammalian cells. The major active enzyme of this class in bacteria, and specifically, E. coli is endonuclease type III. This enzyme is part of a family of lyases that cleave carbon-oxygen bonds.

<span class="mw-page-title-main">ERCC6</span> Gene of the species Homo sapiens

DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.

<span class="mw-page-title-main">DNA-3-methyladenine glycosylase</span> Protein-coding gene in the species Homo sapiens

DNA-3-methyladenine glycosylase also known as 3-alkyladenine DNA glycosylase (AAG) or N-methylpurine DNA glycosylase (MPG) is an enzyme that in humans is encoded by the MPG gene.

<span class="mw-page-title-main">NTHL1</span> Protein-coding gene in the species Homo sapiens

Endonuclease III-like protein 1 is an enzyme that in humans is encoded by the NTHL1 gene.

<span class="mw-page-title-main">NEIL1</span> Protein-coding gene in the species Homo sapiens

Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.

<span class="mw-page-title-main">MBD4</span> Protein-coding gene in the species Homo sapiens

Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.

<span class="mw-page-title-main">NEIL2</span> Gene of the species Homo sapiens

Endonuclease VIII-like 2 is an enzyme that in humans is encoded by the NEIL2 gene.

<span class="mw-page-title-main">DNA demethylation</span> Removal of a methyl group from one or more nucleotides within a DNA molecule.

For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence.

<span class="mw-page-title-main">H2TH domain</span>

In molecular biology, the H2TH domain is a DNA-binding domain found in DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway. These enzymes are primarily from bacteria, and have both DNA glycosylase activity EC 3.2.2.- and AP lyase activity EC 4.2.99.18. Examples include formamidopyrimidine-DNA glycosylases and endonuclease VIII (Nei).

DNA-deoxyinosine glycosylase is an enzyme with systematic name DNA-deoxyinosine deoxyribohydrolase. This enzyme is involved in DNA damage repair and targets hypoxanthine bases.

References

  1. ↑ Liu Y, Prasad R, Beard WA, Kedar PS, Hou EW, Shock DD, Wilson SH (2007). "Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase β". Journal of Biological Chemistry. 282 (18): 13532–13541. doi: 10.1074/jbc.M611295200 . PMC   2366199 . PMID   17355977.
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