The enzyme DNA-(apurinic or apyrimidinic site) lyase, also referred to as DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase (systematic name) or DNA AP lyase (EC 4.2.99.18)
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.
Other names for DNA AP lyase include: AP lyase; AP endonuclease class I; endodeoxyribonuclease (apurinic or apyrimidinic); deoxyribonuclease (apurinic or apyrimidinic); E. coli endonuclease III; phage-T4 UV endonuclease; Micrococcus luteus UV endonuclease; AP site-DNA 5'-phosphomonoester-lyase; and X-ray endonuclease III.
Structural studies
Since DNA AP lyase is a class of structures who have numerous target genes that encode for different variations of the enzyme, there is no one single enzyme structure that can be used as an example that encompasses all versions of the enzyme. As of March 2015
99structures
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
have been solved for this class of enzymes. Examples from
PDB are the accession codes , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
Mechanism
AP lyase enzymes catalyze reactions analogous to β-elimination reaction. Initially, AP hydrolyses, such as
apurinic or apyrimidinic endonuclease I contain a Mg
2+ active site that cleaves the DNA on the 5'-side, yielding a 5'-deoxyribosephosphate and 3'-OH.
An AP site in DNA appears when the glycosylic bond that connects the purine or pyrimidine
base to the deoxyribose sugar is cleaved.
This reaction is referred to as depurination or depyrimidination. The sugar at the AP site is a highly unstable cyclic carboxonium ion that undergoes rapid hydrolysis to yield a diastereomeric mixture of 2-deoxy-α-
Dribose and 2-deoxy-β-
D-ribose. AP lyase enzymes could be trapped on both pre-incised and unincised AP DNA by a reducing agent such as
sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds applica ...
. Furthermore, the catalytic mechanism of AP lyases, the β-elimination reaction, proceeds through an imine enzyme–DNA intermediate.
Biological function
In ''E. coli'', DNA AP lyase (endonuclease III) helps repair oxidative damage to DNA bases by catalyzing the excision of the damaged pyrimidines and purines from ring saturation or opening from the DNA backbone. This damage can be caused by non-enzymatic
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolys ...
, and/or exposure to ionizing radiation.
Both UV endonuclease V from
bacteriophage T4
Escherichia virus T4 is a species of bacteriophages that infect ''Escherichia coli'' bacteria. It is a double-stranded DNA virus in the subfamily '' Tevenvirinae'' from the family Myoviridae. T4 is capable of undergoing only a lytic lifecycle ...
(UV endonuclease V) and UV endonuclease III from ''E. coli'' catalyze N- glycosylase and the 3‘-abasic endonuclease reactions. Bacteriophage T4 and ''Micrococcus luteus'' UV endonucleases were actually shown not to be under the class of "endonuclease," but rather were β-elimination catalysts for reactions at AP sites at the C
3'-O-P bond—thus, classifying them as AP lyases. Phage-T4 UV endonucleases also catalyze the reaction of the δ-reaction, nicking C
5'-O-P bond at AP sites, although this reaction is slow and the enzyme should still be classified as AP lyase. This open ring allows the substitution of the correct base by other enzymes.
DNA AP lyase activity is documented to have similar function in both ''E. Coli'' and in humans. A
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
of endonuclease III, human endonuclease III homolog 1, or hNTH1 functions similarly in humans as its homolog does in ''E. Coli''.
Disease relevance
DNA damage is ubiquitous amongst all forms of life. There is an estimated 1 x 10
−4 to 1 x 10
−6 mutations per human
gamete
A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...
, which follows to finding at least one mutation at a specific
locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
per one million gametes.
DNA is the only biologic molecule that relies solely on repair of existing molecules, and is the largest molecule that can continue to function albeit numerous mutations; thus, mutations accumulate over time.
However without this repair, conditions such as
UV-sensitive syndrome,
xeroderma pigmentosum
Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in su ...
,
and
Cockayne syndrome may arise.
Examples
The least severe of the three, people suffering from UV-sensitive syndrome experience UV-hypersensitivity. The syndrome arises from a mutation in the
KIAA1530 protein. Unlike other severe conditions involving
skin cancer
Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
s and significantly reduced lifespan,
this condition may result in freckles, and other skin blemishes, but does not increase likelihood of attracting a skin cancer.
This condition is so rare that it has been documented to occur in seven individuals
worldwide. However, it is speculated that this condition is understudied, and there are, in fact, more individuals living with the syndrome.
Xeroderma pigmentosum or XP is a rare genetic disorder that occurs worldwide. On affected people, exposure to UV radiation, especially from the sun is limited and solar pigmentations and xerosis occur. The affected may lose eyebrows, become bloodshot in the eyes, and in extreme, untreated cases, may result in extreme photo-damage resulting in skin cancers and decreased lifespan due to
metastatic
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
malignant
melanoma and
squamous cell carcinoma.
However, some studies report that experimental treatments with repair enzyme T4 endonuclease V
and oral isotretinoin may be useful in preventing skin cancer acquired from the disorder.
If transcription-coupled repair is lost, it has little effect on mutagenesis; however, this has severe implications on
progeroid syndromes, especially in genes encoding CSA and CSB proteins. Mutations in these genes cause Cockayne Syndrome, which is characterized by early cessation of growth and development, leading to severe and progressive neurodysfunction associated with demyelination, sensorineural hearing loss, cataracts, cachexia, and frailty.
The average lifespan of patients with the disease is 12 years.
For CS Type II patients who have little neural growth after birth, the lifespan is significantly decreased to 7 years after birth. This condition can occur alongside xeroderma pigmentosum, resulting in xeroderma pigmentosum-cockayne syndrome (XP-CS).
See also
*
OGG1
*
NEIL1
*
NEIL2
*
Endonuclease
*
AP endonuclease
Apurinic/apyrimidinic (AP) endonuclease is an enzyme that is involved in the DNA base excision repair pathway (BER). Its main role in the repair of damaged or mismatched nucleotides in DNA is to create a nick in the phosphodiester backbone of t ...
References
Further reading
* https://www.wikigenes.org/e/gene/e/328.html
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Lyases
EC 4.2.99
Enzymes of known structure