N6-adenosine-methyltransferase 70 kDa subunit (METTL3) is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''METTL3''
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 ...
.
METTL3 is located on the human chromosome 14q11.2 (Cancer Biology) and out of the METTL protein family, it is the most studied.
This gene encodes the 70 kDa subunit of MT-A which is part of N6-adenosine-
methyltransferase
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Ro ...
. This enzyme is involved in the post-transcriptional methylation of internal
adenosine
Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...
residues in eukaryotic
mRNAs
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the p ...
, forming
N6-methyladenosine
''N''6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s, and is an abundant modification in mRNA and DNA. It is found within some viruses, and most eukaryotes including mammals, insects, plants and yeast. I ...
(m
6A).
METTL3 forms the m
6 a methyltransferase complex with METTL14 and WTP and is responsible for a majority of the m
6a modifications of mRNA.
The most common modification being the catalyzation of m
6a with the methyltransferase complex.
METTL3 is expressed in a variety of normal tissues, such as the lymphoid, testis, prostate and fallopian tube tissues. The enzyme is also responsible for mechanisms related to tumor development, RNA stability and maturation, and has suggested roles in ensuring animal survival.
Function
The m6A methyltransferase complex
In the m
6a methyltransferase complex (MTC), METTL3 is a part of the m
6A “writers” and is a core catalytic component.
METTL3 interacts with ''S-''adenosylmethionine (SAM), a methyl donor to catalyze the formation of the MTC complex via methyl transfer.
METTL3 forms the heterodimer complex with METTL3, binds to SAM and interacts with substrate RNA to transfer methyl groups to target RNA. The complex can also bind to target RNA using WTAP. After a METTL3-METTL14-WTAP complex forms, METTL3 can bind to RBM15. Then, MTC can be recruited at specific sites in the RNA.
In cancer
METTL3 acts as an m6a methyltransferase in cancer, mostly as an oncogene, and sometimes a tumor suppressor. In most examples, METTL3 promotes the initiation and development of cancers such as lung, liver, gastric, prostate and breast cancer. METTL3 does so through applying m6a modifications on crucial mediators and transcripts. An example of this is METTL3 expression in pancreatic cancer. In pancreatic cancer, METTL3 expression applies m6a modifications onto the oncogene primary miR-25, provoking malignant transformation via enhanced maturation of the miRNA.
In a few cases, METTL3 acts as a tumor suppressor. The m6a mRNA modifications from METTL3 can promote tumor suppressor proliferation, migration, and invasion. In colorectal cancer, METTL3 promotes the tumor suppressor through p38/ERK pathways.
References
Further reading
*
*
*
*
{{gene-14-stub