Mgmt Housekeeping Genes Present In All Human Beings Biology Essay
MGMT is O-6-methylguanine-DNA methyltransferase OR methylguanine-DNA methyltransferase, one of the house maintaining cistrons which is present in all human existences and gets expressed during DNA harm ( 8 ) .It encodes enzyme Methylated-DNA — protein-cysteine methyltransferase, a DNA fix enzyme belonging to MGMT household ( 1 ) .. Methylation of booster part of this cistron has been the ground for the malignant neoplastic disease in Pharynx, lungs and prostate ( 2-4 ) .
1.2 BASIC Details:
Fig 1. X-RAY STRUCTURE OF HUMAN O-6- ALKYLGUANINE-DNA ALKYLTRANSFERASE ( PDB ID: 1QNT )
The enzyme consists of 176 amino acid in a individual concatenation A.
Link to nucleotide Sequence:
hypertext transfer protocol: //www.ncbi.nlm.nih.gov//nuccore/NC_000010.10? report=fasta & A ; from=131265454 & A ; to=131565783
Methylated-DNA — protein-cysteine methyltransferase is a DNA fix enzyme and helps in forestalling mutants and cell decease by taking the mutagenic and cytotoxic adducts formed by alkylation of Gs by the carcinogen O6-methylguanine ( 6 ) .
It can take really complex alkyl group like ethyl- , propyl- , butyl- , benzyl- and 2-chloroethyl groups.
It gives tumour opposition to alkylating chemotherapies ( 5 ) .
Act as a biomarker in observing the malignant neoplastic disease ( 5 ) .
This cistron is omnipresent and the sum varies in different cells and in tumour cells. The cistron does non incorporate a TATA box or CAT box in its booster part but has GC rich parts chiefly in parts 823 -936 ( 89 % ) and 979-1031 ( 90 % ) . The booster part is similar to that of the booster parts of housekeeping cistrons, i.e. it is needed in all cell and is least influenced by environmental factors. The booster part is found in the 1157b of the cistron. The sequence CCGCCC is the cistron booster part in the 53 bp part ( of what? ) , AIDSs as the part for the binding of RNA polymerase II ( 11 ) .There are two putative AP ( what is AP ) binding sites for the cistron AP-1and AP-2, two glucocorticoid response elements for the booster part of the cistron and activates the written text. In the presence of carcinogens and in tumour cells it ( WHAT? ) gets transactivated ( 12 ) . Many factors like ionisation and chemicals like Decadron, 2-chloroethyl-/V-nitrosourea and other mutagens, ionisation radiation induced MGMT-CAT activation ( 13 ) .There by formation of messenger RNA, which translate into the enzyme methylguanine-DNA methyltransferase chiefly involved in DNA fix mechanism.
MGMT initiates a really simple human DNA fix tract. Alkylation of Deoxyribonucleic acid at O6-G ( Guanine ) , O4-T ( Thymine ) and O2-T places by carcinogen O6-MeG ( O6-Methylguanine ) ( 7 ) is the first measure towards malignant neoplastic disease formation. The alkyl group from O6-MeG goes and binds with the O ( 6 ) place of the G and signifiers O6-ethyl G which forms O6- million: T mis fit, taking to a G: C A: Thymine passage that is associated with both mutagenesis and carcinogenesis. At this times the enzymes comes in action, it removes the alkyl group from the O ( 6 ) place of the G and attaches covalently to the enzyme ‘s cystene residue nowadays in the active site ( Cys145 in the human protein ) in a stoichiometric reaction. Finally the protein go inactive, since the enzyme loses its critical belongingss after the reaction it is called as self-destruction reaction ( 8, 10 ) .
Fig 1: binding of Alkyl to the G and formation of O6- million: Thymine
Deoxyribonucleic acid ( incorporating 6-O-methylguanine ) = DNA ( without 6-O methylguanin
+ Protein L-cysteine + protein S-methyl-L-cysteine ( 1 )
Fig 2: Removal of Alkyl group by enzyme ( 9 )
The major carcinogen from baccy fume nitrosamine 4- ( methylnitro-samino ) -1- ( 3-pyridyl ) -1-butanone besides called nicotine-derived nitrosamine ketone ; NNK ) was found to be responsible for the methylation caused in the booster part of many tumour suppresser cistrons which in bends inactivates the cistron taking to malignant neoplastic disease formation ( 14 ) .The carcinogen from smoke 4- ( methylnitrosamino ) -1- ( 3-pyridyl ) -1- methyl ethyl ketone found in baccy fume signifiers O6-guanine alkyl adducts and is removed by MGMT ( 2 ) . ( str )
Mechanism Of booster Methylation by NNK
Methylation in promoter part does non do any change in the cistron but inactivates its normal map. There is really less cognition about the cause for booster methylation in MGMT ( 15-18 ) .There is a strong positive association between MGMT methylation and baccy smoke ( 20 ) .
Deoxyribonucleic acid methyltransferase 1 ( DNMT1 ) is an enzyme which causes methylation in DNA and the accretion of this enzyme in the karyon, binds to the CpG booster part taking to hyper methylation and was found in tobacco users. NNK is one such carcinogen from the coffin nail which can do accretion of that enzyme. This enzyme is phosphorylated by animal starch synthase kinase 3I? ( GSK3I? ) which takes up I?-transducin repeat-containing protein ( I?TrCP ) doing debasement of DNMT1via ubiquitin-proteosome system. NNK activates the AKT tract which inhibits GSK3I? , which is involved in the phosphorylation of its substrate protein ( here DNMT1 ) , which in bend recruit I?TrCP to transport out DNMT1 debasement. NNK besides facilitates translocation of I?TrCP with the aid of shuttling protein lending to farther accretion of the DNMT.This unnatural accretion causes hypermethylation in the CpG booster part ( 14 ) . ( needs luxuriant account )
NNK induced booster methylation
Interaction Mechanism of MGMT with other cistron
MGMT methylation leads to the mutant in p53 in lung malignant neoplastic disease. Many carcinogens like PAHs, nitrosamines, BPDE, NNK from coffin nail fume signifier DNA adducts with Gs in the CpG site. Among this NNK was the strongest carcinogen which forms ethyl adducts at the O6 place of G and pyridyloxobutyl adduct, which in normal instance is repaired by MGMT.As the MGMT is methylated and inactive, it can non mend the cistron as in normal province and do G-A mutant in lungs taking to tumor. ( 16 )
P16 is a cell growing regulative cistron frequently seen methylated in lung malignant neoplastic diseases along with MGMT in tobacco users. MGMT protect the other cistron purchase taking the carcinogen edge to the G of the cistron. The methylation happening in this cistron booster part makes the cistron inactive thereby forestalling the fix of p16 cistron taking to the formation of cancer.p16 methylation here is formed by NNK ( 18-19 ) .
Change in Pharynx and prostate
In Pharynx and prostate malignant neoplastic disease this cistron was found to be methylated in the booster part associated to smoke ( 3, 4 ) .