MUTYH
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''MUTYH'' (mutY DNA glycosylase) is a human
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that encodes a
DNA glycosylase 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 ste ...
, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the
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 t ...
pathway. The enzyme excises adenine bases from the DNA backbone at sites where
adenine Adenine (, ) (nucleoside#List of nucleosides and corresponding nucleobases, symbol A or Ade) is a purine nucleotide base that is found in DNA, RNA, and Adenosine triphosphate, ATP. Usually a white crystalline subtance. The shape of adenine is ...
is inappropriately paired with
guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...
,
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage. The protein is localized to the nucleus and mitochondria. Mutations in this gene result in heritable predisposition to colon and stomach cancer. Multiple transcript variants encoding different isoforms have been found for this gene.


Location and structure

MUTYH has its locus on the short (p) arm of chromosome 1 (1p34.1), from base pair 45,464,007 to base pair 45,475,152 (45,794,835–45,806,142). The gene is composed of 16 exons and has a size of 546 amino acids and is approximately 7.1kb. The presence of disulfide crosslinking gives rise to a complex crystal structure of the MUTY-DNA. The protein structure of the MUTYH gene has its N-terminal on the 5' and the C-terminal on the 3'. Within the N-terminal, there is a helix-hairpin-helix and pseudo helix-hairpin-helix in addition to an iron cluster motif.


Mechanism

Repair of oxidative DNA damage is the result of a collaborative effort of MUTYH,
OGG1 8-Oxoguanine glycosylase, also known as OGG1, is a DNA glycosylase enzyme that, in humans, is encoded by the ''OGG1'' gene. It is involved in base excision repair. It is found in bacterial, archaeal and eukaryotic species. Function OGG1 is th ...
, and MTH1. MUTYH acts on the adenine base that is mispaired to 8-oxoG, while OGG1 detects and acts on 8-oxoG, removing it.
TP53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
transcriptionally regulates MUTYH and may potentially act as a regulator for p53.


Expression

MUTYH is overexpressed in CD4-T cells, the
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
, the colon, where cells frequently divide, and the rectum. There is evidence of MUTYH expression in kidney, intestinal, nervous system and muscle tissues.


Protein interactions

MUTYH has been shown to interact with
Replication protein A1 Replication protein A 70 kDa DNA-binding subunit is a protein that in humans is encoded by the ''RPA1'' gene. Interactions Replication protein A1 has been shown to interact with: * BRCA2, * BLM, * MCM2, * MCM4, * MCM6, * MCM7, * MU ...
,
PCNA Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase delta, DNA polymerase δ in eukaryotic cell (biology), cells and is essential for replication. PCNA is a homotrimer and achieves its ...
and
APEX1 DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the ''APEX1'' gene. Apurinic/apyrimidinic (AP) sites (also called "abasic sites") occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging age ...
. MUTYH and OGG1 excision of bases causes the formation of apurinic/ apyrimidinic sites ( AP sites). These sites are mutagenic in nature and require constant and immediate repair which is achieved by the active involvement of protein complexes that repair the AP site via short and long patch repair pathways. The short patch repair pathway employs POLB (
DNA polymerase beta DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the ''POLB'' gene. Function In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA mainte ...
), APE1, XRCC1,
PARP1 Poly DP-ribosepolymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly DP-ribosesynthase 1 is an enzyme that in humans is encoded by the ''PARP1'' gene. It is the most abundant of the PARP family of enzymes, accounting for 90% o ...
with the addition of either the
LIG1 DNA ligase 1 also DNA ligase I, is an enzyme that in humans is encoded by the ''LIG1'' gene. DNA ligase 1 is the only known eukaryote, eukaryotic DNA ligase involved in both DNA replication and DNA repair, repair, making it the most studied of th ...
or LIG3 genes. When an insertion of one nucleotide occurs, the enzyme
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 ...
(APEX/APE1) cuts out the mismatched base pairs at the AP site and this causes the evolvement of 5'dRP (5' deoxyribose phosphate), a terminal blocking group, and 3'-OH ( 3' hydroxyl end). POLB is required to remove the 5'dRP, and it does this by enzymatic activity, namely polymerase and dRP lyase. DNA ligase is used to seal the fragments after dRP excision causes the formation of 5'PO4 that is necessary to form the
phosphodiester bond In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups () in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage . Discussion of phosphodiesters is d ...
s of DNA. The purpose of PARP1 and XRCC1 in the single strand break repair pathway, is to stabilize the strands of DNA while they undergo repair, synthesis, gap-filling and ligation. PARP1 acts as a recruit agent for XRCC1. The nick sealing of the strands is accomplished by the formation of LIG1 (DNA ligase 1) and/or LIG3/ XRCCI complex that attach to processed end of the corrected strands and reinstate the original conformation of the strand. Long patch repair comes into play when more nucleotides are involved, ranging from 2 to 12. It is hypothesized that Polymerase 𝜹 (POLD) and Polymerase 𝛆 (POLE), assisted by the PCNA (
proliferating cell nuclear antigen Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the D ...
) in conjunction with
replication factor C The replication factor C, or RFC, is a five-subunit protein complex that is required for DNA replication. The subunits of this heteropentamer are named Rfc1, Rfc2, Rfc3, Rfc4, and Rfc5 in ''Saccharomyces cerevisiae''. RFC is used in eukaryo ...
(RFC) that acts as a stabilizer and places newly synthesized nucleotides on the DNA strand. Both the polymerases repair the DNA by employing the strand displacement synthesis mechanism. This mechanism occurs downstream a DNA strand and the 5' is transformed into a "flap intermediate" causing it to be "displaced". FEN1 ( flap structure-specific endonuclease 1), a nuclease, removes the displaced strand and this results in a ligatable strand of DNA.Long patch repair, like short patch repair, includes the use of APE1 and PARP1 and LIG1. The repair pathway is partially determined by the amount of ATP present after the removal of the deoxyribose phosphate end. The long patch repair pathway is preferred under conditions of low ATP concentration while the short repair pathway is preferred under high concentrations of ATP. Other notable interactions include MUTYH and
Replication protein A Replication protein A (RPA) is the major protein that binds to single-stranded DNA (ssDNA) in eukaryotic cells. In vitro, RPA shows a much higher affinity for ssDNA than RNA or double-stranded DNA. RPA is required in replication, recombination ...
is a single strand binding protein that prevents the annealing of DNA during replication, it also plays a role as an activator for damage repair on DNA. There is a hypothetical relation between the interaction of Mismatch Repair proteins (MMR) such as MSH 2,3 and 6, MLH1, PMS1 and 2, and MUTYH in which the proposed result of their partnering is to increase susceptibility to cancer.


Chemical interactions

The gene interacts with the following chemicals: a)
Carbon tetrachloride Carbon tetrachloride, also known by many other names (such as carbon tet for short and tetrachloromethane, also IUPAC nomenclature of inorganic chemistry, recognised by the IUPAC), is a chemical compound with the chemical formula CCl4. It is a n ...
: decreased expression of MUTYH mRNA b)
Ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
: When treated together with dronabinol) increased expression of MUTYH mRNA. When used alone, it has conflicting results of decreased and increased the MUTYH mRNA. c)
Ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. Ethinylestradiol was widely used for various indications such as the treatment of menopausal symptoms, gynecological ...
: When used alone it results in the increased expression of MUTYH mRNA.When treated together with tetrachlorodibenzo p dioxin, there is increased expression of MUTYH mRNA. d)
Tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...
: affects MUTYH


Related conditions

The table of the Gene-phenotype associations summarizes the diseases/conditions that arise from mutations in MUTYH Mutations in the MUTYH gene cause an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
disorder similar to
familial adenomatous polyposis Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon ...
(also called MUTYH-associated polyposis). Polyps caused by mutated MUTYH do not appear until adulthood and are less numerous than those found in patients with
APC gene Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the ''APC'' gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E- ...
mutations. Both copies of the MUTYH gene are mutated in individuals who have autosomal recessive familial adenomatous polyposis i.e., the mutations for the MUTYH gene is biallelic. Mutations in this gene affect the ability of cells to correct mistakes made during
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
. Most reported mutations in this gene cause production of a nonfunctional or low functioning glycosylase enzyme. When
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 t ...
in the cell is compromised, mutations in other genes build up, leading to cell overgrowth and possibly tumor formation. The two most common mutations in
Caucasian Caucasian may refer to: Common meanings *Anything from the Caucasus region or related to it ** Ethnic groups in the Caucasus ** ''Caucasian Exarchate'' (1917–1920), an ecclesiastical exarchate of the Russian Orthodox Church in the Caucasus re ...
Europeans are exchanges of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s (the building blocks of proteins) in the enzyme. One mutation replaces the amino acid
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
with
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
at position 179 (also written as p.Tyr179Cys (p.Y179C)) or, when describing the nucleotide change, written as c.536A>G). The other common mutation switches the amino acid
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
with
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
at position 396 (also written as p.Gly396Asp (G396D) or c.1187G>A)). The association of the gene with gastric cancer is somewhat indirect and multifactorial. When a subject is infected with
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
(''H. pylori''), the bacteria cause the formation of free oxygen radicals that are present in the gastric mucosa and this increases the propensity of the genes to incur oxidative damage . A study of 95 cases of patients who had sporadic cancers, initiated by the presence of H. pylori, and two of the 95 patients had biallelic mutation of the MUTYH gene. The somatic missense mutations for the first identified cancer occurred at codon 391, in which there was a change in the nucleotide bases from CCG (codon for amino acid proline) to TCG (codon for amino acid serine), while the second cancer had a nucleotide base change at codon 400 from CAG (codon for amino acid glutamine) to GGG (codon for amino acid arginine). The mutations were found to be highly conserved in the Nudix hydrolase domain of MUTYH. These amino acid mutations provide the basis for the somatic mutations in the gastric system.
Pilomatricoma Pilomatricoma is a benign skin tumor derived from the hair matrix. These neoplasms are relatively uncommon and typically occur on the scalp, face, and upper extremities. Clinically, pilomatricomas present as a subcutaneous nodule or cyst with unr ...
has been noted in a case that concerned two siblings who were the offspring of consanguineous parents. The siblings had a 2 base pair homozygous insertion on the MUTYH gene ( exon 13). Consequently, a frameshift occurred due to the insertion and a premature stop codon was read at 438 on the gene. Pilomatricoma was the phenotypic manifestation of this mutation. One of the siblings was also found to have rectal adenocarcinoma. It is worthy to note that CTNNB1, a gene associated with pilomatricoma, was also investigated. However, no mutations in this gene were found, thereby dismissing it as a possible cause for this case. There is an established correlation between aging and the elevation 8-oxoG concentrations, particularly in organs that exhibit reduced cell proliferation such as the kidneys, liver, brain and lungs. Presence of 8-oxoG also occurs in large concentrations in patients with neurological conditions such as Alzheimer's, Parkinson's and Huntington's disease. MUTYH causes immoderate formation of single stranded breaks via base excision repair, under acute oxidative stress conditions. When the 8-oxoguanine species accumulate and increase in concentration in the neurons, MUTYH responds by triggering their degeneration.


See also

* NTHL1 *
NEIL1 Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the ''NEIL1'' gene. NEIL1 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by ...


References


Further reading

* * * * * * * * * * * * *


External links

* *
GeneCard

Hereditary Colorectal Cancer Syndromes

LOVD database
{{Webarchive, url=https://web.archive.org/web/20160304031950/http://chromium.lovd.nl/LOVD2/colon_cancer/home.php?select_db=MUTYH , date=2016-03-04