microRNA

What are microRNAs?

MicroRNAs constitute a recently discovered class of non-coding RNAs that play key roles in the regulation of gene expression. Acting at the post-transcriptional level, these fascinating molecules may fine-tune the expression of as much as 30% of all mammalian protein-encoding genes.

Mature microRNAs are short, single-stranded RNA molecules approximately 22 nucleotides in length. MicroRNAs are sometimes encoded by multiple loci, some of which are organized in tandemly co-transcribed clusters.

Transcription and processing of microRNA

MicroRNA genes are transcribed by RNA polymerase II as large primary transcripts (pri-microRNA) that are processed by a protein complex containing the RNase III enzyme Drosha, to form an approximately 70 nucleotide precursor microRNA (pre-microRNA). This precursor is subsequently transported to the cytoplasm where it is processed by a second RNase III enzyme, DICER, to form a mature microRNA of approximately 22 nucleotides .The mature microRNA is then incorporated into a ribonuclear particle to form the RNA-induced silencing complex, RISC, which mediates gene silencing.

Figure: MicroRNA biogenesis

MicroRNA and gene expression MicroRNAs usually induce gene silencing by binding to target sites found within the 3’UTR of the targeted mRNA. This interaction prevents protein production by suppressing protein synthesis and/or by initiating mRNA degradation. Since most target sites on the mRNA have only partial base complementarity with their corresponding microRNA, individual microRNAs may target as many as 100 different mRNAs. Moreover, individual mRNAs may contain multiple binding sites for different microRNAs, resulting in a complex regulatory network. The function of microRNAs MicroRNAs have been shown to be involved in a wide range of biological processes such as cell cycle control, apoptosis and several developmental and physiological processes including stem cell differentiation, hematopoiesis, hypoxia, cardiac and skeletal muscle development, neurogenesis, insulin secretion, cholesterol metabolism, aging, immune responses and viral replication. In addition, highly tissue-specific expression and distinct temporal expression patterns during embryogenesis suggest that microRNAs play a key role in the differentiation and maintenance of tissue identity. MicroRNA as disease biomarkers In addition to their important roles in healthy individuals, microRNAs have also been implicated in a number of diseases including a broad range of cancers, heart disease and neurological diseases. Consequently, microRNAs are intensely studied as candidates for diagnostic and prognostic biomarkers and predictors of drug response. MicroRNA research MicroRNAs were first reported in mammalian systems in 2001. In the latest release of miRBase (v.15), more than 14000 microRNAs have been annotated, highlighting the rapid growth of this field of research. However, the functions of most of these microRNAs still remain to be discovered. The challenges of studying microRNAs are two-fold. First, microRNAs are very short (~22 nt). This means that traditional DNA-based methods are not sensitive enough to detect these sequences with any reliability. Second, closely related microRNA family members differ by as little as one nucleotide, emphasizing the need for high specificity and the ability to discriminate between single nucleotide mismatches.

Cancer and genes

Some genes control when new cells are made and old cells die, and repair damaged DNA. Changes (mutations) in these genes can increase the risk of cancer developing.

There are two types of mutations, called acquired mutations and inherited mutations. Acquired mutations happen during a person’s lifetime, and can’t be passed on to their children. They can happen by chance when a cell is multiplying or because a gene is damaged. Some substances, such as cigarette smoke, can increase the chance of gene mutations.

Most cancers are caused by a build-up of acquired mutations during a person’s lifetime. These are called sporadic cancers.

Inherited mutations are gene mutations that you are born with. They can be passed on to your children. Inherited gene mutations that make a cancer more likely to develop are called cancer susceptibility genes. If you inherit these genes, it doesn’t mean you’ll definitely get cancer, but you may be at an increased risk of developing it.

There are inherited cancer genes for some cancers, including breast, bowel, ovarian and womb.

Other cancers, including prostate, pancreatic and testicular, happen in some families more than usual. But specific inherited cancer genes haven’t been found for these cancers yet.

Genes and how they work

Our body is made up of tiny building blocks, called cells. Cancer develops when some cells are damaged and our body can’t repair them. The damaged cells keep growing out of the body’s control. These are cancer cells.

There are genes in every cell. All cancers are caused by changes (mutations) in genes. Genes contain the information a cell needs to work properly. This information is in a code called DNA (deoxyribonucleic acid).

Our body needs to make new cells to replace old or damaged ones. Genes control this process. They also tell cells how to repair damage. If a cell can’t be repaired, or is not needed, genes inside the cell tell it to die.

The genes that control cell growth, repair and death are called oncogenes and tumour suppressor genes. Mutations in these types of gene can increase the chance of cancer developing.

Oncogenes

These genes encourage cells to grow and multiply. A mutation in an oncogene can lead to a cell growing and multiplying out of control.

Tumour suppressor genes

These genes help protect against cancer. They control cell growth. They also repair damage to DNA.

If a cell has a mutation in a tumour suppressor gene, it may lose the ‘brakes’ on its growth. The cell can then multiply out of control.

Some tumour suppressor genes repair damage to DNA. Doctors call them DNA repair genes or caretaker genes.

When there is a mutation in a DNA repair gene, the cell can’t repair damage to itself. So cancer is more likely to develop.

Acquired mutations

Most cancers develop because of gene mutations that happen during a person’s lifetime. Doctors call these mutations acquired mutations.

Acquired gene mutations happen in the part of the body where the cancer later develops. For example, gene mutations happen in the lungs before lung cancer develops.

Many things can cause gene mutations. These include:

• getting older
• things in our environment such as tobacco and sunlight
• our hormones
• our diet.

Doctors call substances that increase the chance of gene mutations carcinogens. Radiation and the chemicals in cigarette smoke are examples of carcinogens.
Usually, several gene mutations must happen in a cell before cancer develops. This can take many years. This is why cancer is more common in older people. Cancers caused by gene mutations that happen during someone’s lifetime are called sporadic cancers.

Genes and inheritance

We inherit our genes from our parents. Everyone has two copies of each gene; one from their mother and one from their father.
Some people are born with a gene mutation that puts them at higher risk of getting cancer. Inherited mutations that make cancer more likely are called inherited cancer genes. Doctors may also call them cancer predisposition genes or cancer susceptibility genes.

If you inherit a gene mutation, it is in all your cells. This includes the sperm cells in men and the egg cells in women. So there is a 50% (1 in 2) chance of passing the gene mutation on to any children.
Inheriting a cancer gene doesn’t mean you have cancer. But, it does mean you have an increased risk of developing certain types of cancer. Further gene changes (acquired mutations) need to happen for a cancer to develop.
Doctors call cancers that develop in a family because of an inherited cancer gene inherited cancers or hereditary cancers.
Inherited cancers often develop at a younger age than sporadic cancers. Most inherited cancer genes don’t increase cancer risk until people are adults. But a few inherited cancer genes increase the risk of cancer in children. We have more information about genetic testing in children.

Can cancer genes ‘skip’ a generation?

Cancer genes cannot ‘skip’ a generation. There is a 1 in 2 (50%) chance of inheriting the gene from one of your parents. So you either inherit it or you don’t. If you don’t inherit the gene, you can’t pass it on to your children. But not everyone with the mutation develops cancer. So it can seem that the cancer skipped one generation.
The gene mutations for female cancers such as breast or ovarian cancer can pass through the father’s side of the family. Men who have the cancer gene for breast and ovarian cancer often don’t develop cancer. But they still have a 50% chance of passing the cancer gene on to their children.
If a daughter inherits a cancer gene from her father and develops breast cancer, it can seem as if the cancer gene has skipped a generation. But this isn’t the case. The mutation can’t skip a generation.

Inherited cancer genes

If a particular type of cancer occurs in a family more than in the general population, some people in the family may have an inherited cancer gene.
Scientists have found inherited cancer genes for some common cancers. These include cancers of the breast, bowel, ovary and womb.
There are other cancers that happen in some families more than usual. These include prostate, pancreatic and testicular cancers. But doctors haven’t found specific inherited cancer genes for these cancers yet.
Sometimes, there are many different types of cancer in a family. Usually, these are sporadic cancers (see above) and are due to risk factors such as age, lifestyle and the environment. But some inherited cancer genes can increase the risk of more than one type of cancer.

When cancers happen together

There are two main patterns where cancers happen together:

• breast and ovarian cancer
• bowel and womb cancer (sometimes with cancers of the ovary, stomach or kidney).

Other rare patterns of cancers can happen.

Low-risk genes

Not all families with more cancers than usual have an inherited cancer gene. But some families may share several genes, which increase their risk of certain cancers. These genes have a weaker effect on the risk of cancer than inherited cancer genes. They are sometimes called low-risk or low-penetrance genes.
Scientists have found several of these genes. But the effect of each gene on its own is small. And there aren’t tests available to check for them. Researchers are trying to find out how these genes interact with other risk factors to affect cancer risk.

DNA

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).
The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences.
DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.
An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone.

Credit: U.S. National Library of Medicine

Gene

A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes.
Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genes are made up of DNA. Each chromosome contains many genes.

Credit: U.S. National Library of Medicine