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]
Lesions processed by BER
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
- Oxidized bases: 8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG, FapyA)
- Alkylated bases: 7-methylguanosine
- Deaminated bases: 5-methylcytosineare more difficult to recognize, but can be repaired by mismatch-specific glycosylases)
- Uracil inappropriately incorporated in DNA or formed by deamination of cytosine[2]
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
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
Flap endonuclease
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]
Links with cancer
Defects in a variety of DNA repair pathways lead to cancer predisposition, and BER appears to follow this pattern.
Epigenetic deficiencies in cancers
MBD4
MBD4 expression is reduced in almost all colorectal
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
Links with cognition
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
- DNA mismatch repair
- DNA repair
- Homologous recombination
- Non-homologous end joining
- Nucleotide excision repair
- Host-cell reactivation assay
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External links
- Base+Excision+Repair at the U.S. National Library of Medicine Medical Subject Headings (MeSH)