Single-strand selective monofunctional uracil DNA glycosylase is an enzyme that in humans is encoded by the SMUG1 gene. [4] [5] [6] SMUG1 is a glycosylase that removes uracil from single- and double-stranded DNA in nuclear chromatin, thus contributing to base excision repair. [6]
SMUG1 is an important uracil-DNA glycosylases that process uracil in DNA. SMUG1 function is to remove U or its derivatives from DNA. SMUG1 is able to excise uracil from both single- and doubledstranded DNA. [7] Other DNA glycosylases linked to U removal are UNG, TDG and MBD4. [8] Uracil-DNA repair is essential to protect against mutations. Current evidence suggests that UNG and SMUG1 are the major enzymes responsible for the repair of the U:G mispairs. [7] [9] [10] Uracil is also introduced into DNA as part of antibody gene diversification and its removal is critical to antibody diversification. UNG is known to be the major player in uracil removal but when depleted SMUG1 can provide a backup for UNG in the antibody diversification process. [11] [12]
In addition to uracil, SMUG1 removes several pyrimidine oxidation products. [13] and has a specific function to remove the thymine oxidation product 5-hydroxymethyl uracil from DNA. [14]
Low SMUG1 transcripts can impair DNA repair and thus increase mutation rate, enhance chromosomal instability and promote selection of more malignant clones with aggressive behavior. Loss of SMUG1 was shown to increase cancer predisposition in mice study. [15] In addition low SMUG1 transcripts were shown to be potentially correlated with poor survival and linked to aggressive phenotype in breast cancer. [16] Low SMUG1 expression is also associated with BRCA1, ATM, XRCC1, implying genomic instability in SMUG1 low tumors. [16] Preclinical study where SMUG1 depletion has been shown to results in sensitivity to 5-FU chemotherapy. [17]
Low SMUG1 in gastric cancer, however, were showing the opposite result, promoting cancer survival and resistance to therapy. One possible explanation is that in gastric cancer inflammation is the driver for carcinogenesis and low concentrations of SMUG1 can be beneficial in repairing oxidative base damage (commonly seen in inflammatory environment). Thus SMUG1 might have complex roles in carcinogenesis and act differently based on the type of cancer and its properties. [18]
5-Fluorouracil (5-FU) is a widely used in the treatment of a range of common cancers that causes DNA damage via two mechanisms. FU is thought to kill cells via the inhibition of thymidylate synthase and also deprive cells of TTP during DNA replication, which leads to the introduction of uracil in DNA causing the fragmentation of newly synthesized DNA. Also, 5-FU is directly incorporated into DNA. UNG and SMUG1 are most likely to tackle the genomic incorporation of uracil and 5-FU during replication. Current research suggests that of SMUG1 but not UNG corresponds to increase in sensitivity to 5-FU. It was suggested that SMUG1 can be potentially used as a predictive biomarkers of drug response and a mechanism for acquired resistance in certain types of tumors. [17] [19]
SMUG1 glycosylase is a key enzyme for repairing lesions generated during oxidative base damage. Investigation of SMUG1 expression in gastric cancers showed that overexpressed SMUG1 was correlated with patients’ poor survival. In gastric cancer inflammation is the driver for carcinogenesis. And thus one possible explanation is that cancer cells are under considerable oxidative stress compared to normal cells and unregulation of SMUG1 is essential for the repair of oxidative base damage and survival in cancer cells. [18] In this case elevation of SMUG1 as opposed to depletion can be potentially used as a biomarker for survival.
SMUG1 has been shown to interact with RBPMS [20] and with DKC1. [21]
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.
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.
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.
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.
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 or long-patch BER.
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.
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.
Uracil-DNA glycosylase is an enzyme. Its most important function is to prevent mutagenesis by eliminating uracil from DNA molecules by cleaving the N-glycosidic bond and initiating the base-excision repair (BER) pathway.
Cyclin-O is a protein that in humans is encoded by the CCNO gene.
G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDG gene. Several bacterial proteins have strong sequence homology with this protein.
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.
Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.
Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.
Endonuclease VIII-like 2 is an enzyme that in humans is encoded by the NEIL2 gene.
Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it, as seen during class switching. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.
DNA-deoxyinosine glycosylase is an enzyme with systematic name DNA-deoxyinosine deoxyribohydrolase. This enzyme is involved in DNA damage repair and targets hypoxanthine bases.
Double-stranded uracil-DNA glycosylase is an enzyme with systematic name uracil-double-stranded DNA deoxyribohydrolase (uracil-releasing). This enzyme catalyses a specific chemical reaction: it hydrolyses mismatched double-stranded DNA and polynucleotides, releasing free uracil.
DNA base flipping, or nucleotide flipping, is a mechanism in which a single nucleotide base, or nucleobase, is rotated outside the nucleic acid double helix. This occurs when a nucleic acid-processing enzyme needs access to the base to perform work on it, such as its excision for replacement with another base during DNA repair. It was first observed in 1994 using X-ray crystallography in a methyltransferase enzyme catalyzing methylation of a cytosine base in DNA. Since then, it has been shown to be used by different enzymes in many biological processes such as DNA methylation, various DNA repair mechanisms, and DNA replication. It can also occur in RNA double helices or in the DNA:RNA intermediates formed during RNA transcription.
Replication protein A 32 kDa subunit is a protein that in humans is encoded by the RPA2 gene.
Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.
