Snapshot: What is a Gene?

A gene is the basic physical unitof heredity. Every living cell contains genetic information that determines an organism’s development, form, and function. This genetic information is encoded by two macromolecules: DNA and RNA.

DNA consists of two strands of phosphate and sugar molecules connected by pairs of nitrogenous bases to form a double helix structure. The four nitrogenous bases in DNA are adenine, thymine, cytosine, and guanine (abbreviated A, T, C, and G). Genes are sequences of nucleotides (composed of a sugar, a phosphate group, and a base) that provide the instructions that cells need to make molecules that give rise to an organism’s characteristics. Within the nucleus of each cell, DNA is tightly coiled around specialized proteins called histones, forming compact structures called chromosomes. Each gene occupies a particular position, or locus, on a chromosome.

In your cells, you find your DNA in tightly packed X shapped molecules called chromosomes. If you unwind this DNA, you can see it is made of of nucleotide bases.
Genes are sequences of nucleotides that give rise to an organism’s traits. DNA is tightly coiled around structural proteins and compressed to form chromosomes. Chromosomes are housed in the cell’s nucleus and replicated prior to cell division. Figure created by Chloe Soutar using

Most genes contain instructions for creating proteins, amino acid-based macromolecules with a wide range of structures and functions. Among their numerous essential functions, proteins contribute to cell structure and repair, signal transmission between cells, and biochemical reactions within cells. Genes are used to create proteins through a two-step process. Double-stranded DNA is first transcribed into single-stranded messenger RNA (mRNA) that serves as a template for protein synthesis. mRNA exits the nucleus and interacts with cellular machinery called ribosomes. Ribosomes then read mRNA and translate its nucleotide sequence into long chains of amino acids, which then fold to form proteins.

DNA is the instructions to make mRNA, which makes amino acid chains that come together to make protiens which build our bodies.
Genes encode proteins through a two-step process. During transcription, enzymes within the nucleus build single-stranded mRNA molecules that are complementary to one strand of DNA. At this stage, the base thymine (T) is substituted for uracil (U). During translation, cellular structures called ribosomes “read” the mRNA within the cytoplasm and translate the nucleotide sequence into a sequence of amino acids. Linear chains of amino acids then undergo patterns of folding to yield intricate protein structures. Figure created by Chloe Soutar using

An organism’s complete set of genetic material is called a genotype. The human genome is estimated to contain between 20,000 and 25,000 protein-coding genes, varying in size from thousands of nucleotides to over 2 million nucleotides. The complete set of observable traits that results from gene expression is called a phenotype. An organism’s phenotype includes all of its outward characteristics, including height and eye colour, as well as less apparent characteristics such as blood group and intelligence. For example, the genes that determine the amount of pigment in my skin are part of my genotype, but my skin colour is part of my phenotype. Whereas one’s genotype is determined solely by biological factors, one’s phenotype is determined by complex interactions between biological and environmental factors. This distinction between genotype and phenotype is evident in the case of identical twins – even though they have the same genotype, they often look and behave differently due to environmental and lifestyle factors.

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Snapshot: What is poly-ADP-ribose (PAR)?

DNA repair is an important topic when talking about of neurodegenerative disorders. The amount of biochemical stress the brain experiences increases naturally as we age. Some connections have been made between the amount of stresses on the brain and the age people develop neurodegenerative disorders.

Many of these natural stresses can damage DNA. For this reason, many researchers are trying to find ways of helping or fixing DNA repair. Chemicals that effect DNA repair could be used as new drugs. Here, we will focus on just one part of the DNA damage response that has been a great success in cancer drug discovery.

PAR is like a net that pulls in proteins that repair DNA

Poly-ADP-ribose, also called PAR, are long molecules in the cell. They are made of of the same building blocks cells use to store enegry. PARylation is when these long chains of PAR are made and attached to different parts of the cell. This happens in response to many different types of stress. For example, a stress could be if a cell’s DNA is damaged or it is infected with a virus.

When DNA damage happens, PAR molecules are attached on the surface of proteins and can act as a basket to trap other proteins. PAR is made and woven together by PAR polymerase proteins (called PARPs). PARPs add PAR chains all around a site of damage to let other parts of the cell know that damage has happened. This attracts DNA repair proteins to DNA damage by binding to PAR and performing their role to fix the damage.

a lage black fishing net on a white background, it is worn in some placed.
PAR can act like a fishing net that “catches” and pulls in proteins to help fix DNA damage. Image of a fishing net by Nikodem Nijaki on Wikimedia.
To much PAR causes cells to run out of energy

Even though PAR does a good job of signalling that DNA damage has happened, it takes a lot of energy to make. If the damage can not be fixed, the cell will keep trying to make PAR until runs out of energy. This can lead to PAR molecules causing cell death. This effect of too much PAR can be seen in multiple types of neurodegenerative diseases.

A type of cerebellar ataxia called AOA-XRCC1 is known for having higher levels of PAR due to DNA damage. When researchers reduced the amount of PAR in a mouse model of AOA-XRCC1, the mouse had fewer ataxia symptoms and lost fewer neurons. This type of ataxia is caused by a mutation in a protein called XRCC1, which normally helps fix DNA and binds to PAR chains. But in the disease, the XRCC1 gets stuck at DNA along with the long chains of PAR.

These findings may be applicable to other types of ataxia and neurodegenerative disorders because of their link to higher levels of DNA damage. A lot more work to be done on PARylation and its role in neurodegeneration. But a lot of research has been done on PAR in cancer. Many drugs have been FDA approved for cancer patients as safe and effective. Cancer and ataxia are very different diseases. But all the work that has previously been done has laid the groundwork for new research in neurodegeneration.

If you would like to learn more about poly-ADP-ribose , take a look at these resources by the National Cancer Institute and Cancer Research UK.

Snapshot written by Carlos Barba-Bazan and edited by Dr. Ray Truant

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La huntingtine: un nouvel acteur dans l’arsenal de la réparation de l’ADN

Écrit par Dr. Ambika Tewari, Edité par Dr. Mónica Bañez-Coronel, Traduction française par: L’Association Alatax, Publication initiale: 22 novembre 2019

Des mutations dans la protéine huntingtine altèrent la réparation de l’ADN, causant des dommages importants à l’ADN et une expression génétique modifiée.

Notre génome regroupe l’intégralité de notre matériel génétique, qui contient les instructions pour fabriquer les protéines essentielles à tous les processus de l’organisme. Chaque cellule de notre corps, des cellules de la peau qui constituent une barrière de protection essentielle, des cellules immunitaires qui nous protègent des espèces envahissantes et des cellules du cerveau qui nous permettent de percevoir et de communiquer avec le monde contient du matériel génétique. Au début du développement de chaque espèce de mammifère, il existe une prolifération massive de cellules qui permet le développement d’un embryon au stade une cellule à un corps fonctionnel contenant des trillions de cellules. Pour que ce processus se déroule de manière efficace et fiable, les instructions contenues dans notre matériel génétique doivent être transmises avec précision pendant la division cellulaire et son intégrité maintenue pendant toute la durée de vie de la cellule afin de garantir son bon fonctionnement.

De nombreux obstacles entravent la séquence complexe et hautement orchestrée d’événements au cours du développement et du vieillissement, provoquant des altérations pouvant entraîner un dysfonctionnement cellulaire et une maladie. Les sources de dommages à l’ADN internes et externes bombardent constamment le génome. Les rayonnements ultraviolets et l’exposition à des agents chimiques sont des exemples de sources externes, tandis que les sources internes incluent les processus cellulaires pouvant découler, par exemple, des sous-produits réactifs du métabolisme.

Heureusement, la nature a mis au point un groupe spécial de protéines, appelées protéines de réparation et de réparation de l’ADN, qui permettent aux détecteurs de détecter les messages erronés. Ces protéines spécialisées garantissent que les dommages aux molécules d’ADN qui codent nos informations génétiques ne sont pas transmis à la nouvelle génération de cellules lors de la division cellulaire ou lors de l’expression de nos gènes, protégeant ainsi notre génome. De nombreux troubles génétiques sont causés par des mutations du matériel génétique. Cela conduit à un ARN ou une protéine dysfonctionnel avec peu ou pas de fonction (perte de fonction) ou à un ARN ou une protéine avec une fonction entièrement nouvelle (gain de fonction). Étant donné que les protéines de réparation de l’ADN jouent un rôle crucial dans l’identification et le ciblage des erreurs commises dans le message, il va de soi que toute altération du processus de réparation de l’ADN pourrait conduire à une maladie. Dans cette étude, Rui Gao et ses collègues, par le biais d’une vaste collaboration, ont cherché à comprendre le lien qui existe entre la réparation de l’ADN modifiée et la maladie de Huntington.


Un dessin de molécules d'ADN bleues.
Un dessin de molécules d’ADN.

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Snapshot: How does CAG tract length affect ataxia symptom onset?

The instructions our bodies need to grow and function are contained in our genes. These instructions are made up of tiny structures called nucleobases. There are four types of nucleobases in DNA: adenine (A), cytosine (C), guanine (G), thymine (T). By putting these four nucleobases in different orders and patterns, this writes the instructions for our body.

artists drawing of a blue DNA molecule
A cartoon strand of DNA. Image by PublicDomainPictures from Pixabay

Some of the genes contain long sections of repeating ‘CAG” instructions, called CAG tracts. Everyone has repeating CAG tracts in these genes, but once they are over a certain length they can lead to disease. Some ataxias are caused by this type of mutation, including SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. These are often called polyglutamine expansion disorders. This is because “CAG” gives the body instructions to make the amino acid glutamine. You can read more about what is polyglutamine expansion in our past Snapshot about that subject.

For each disorder caused by a CAG expansion mutation, the number of times the CAG is repeated in a particular gene will determine whether someone will develop the disease. Repeat lengths under this number will not cause symptoms and repeat lengths over the threshold will usually lead to ataxia. When someone undergoes genetic testing for ataxia, doctors will be able to tell them the length of these CAG tracts and whether they have a CAG repeat number in one of these genes that is over the threshold. This table gives a summary of different CAG expansion mutations that can lead to ataxia and how the length of the repeat affects age of onset.

 Affected Gene Normal
Repeat Size
Repeat Size
SCA6CACNA1A 4-1821-33

For SCA1, SCA2, SCA3, SCA6, and SCA7; longer CAG tracts are associated with earlier onset.

For SCA12, it is hard to predict the age of onset based on repeat length as SCA12 is so rare. Some individuals with long repeats don’t develop ataxia. One study found that longer CAG tract lengths are associated with earlier onset but that it does not affect the severity of symptoms.

For SCA17, Longer CAG tracts have separately been associated with an earlier age of onset and more severe cerebellar atrophy.

In general, people with longer repeat lengths in ataxia genes are likely to present with ataxia symptoms earlier in life. However, it is important to remember that there are many other factors involved. Other genes may have mutations that either worsen the progression of ataxia or protect against more severe symptoms. Therefore, in individual people, the length of the repeat is not always enough information to determine when that person will start showing symptoms, or how severe these symptoms will be.

If you would like more information about the genetic causes of SCAs, including information about genetic testing and what CAG repeat length might mean, take a look at these resources by the National Ataxia Foundation.

Snapshot written by Anna Cook and edited by Larissa Nitschke.

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Huntingtin: a new player in the DNA repair arsenal

Written by Dr. Ambika Tewari Edited by Dr. Mónica Bañez-Coronel

Mutations in the Huntingtin protein impair DNA repair causing significant DNA damage and altered gene expression

Our genome houses the entirety of our genetic material which contains the instructions for making the proteins that are essential for all processes in the body. Each cell within our body, from skin cells that provide a crucial protective barrier, immune cells that protect us from invading species and brain cells that allow us to perceive and communicate with the world contains genetic material. During early development in every mammalian species, there is a massive proliferation of cells that allows the development from a one-cell stage embryo to a functional body containing trillions of cells. For this process to occur efficiently and reliably, the instructions contained in our genetic material need to be precisely transmitted during cell division and its integrity maintained during the cell’s life-span to guarantee its proper functioning.

There are many obstacles that hamper the intricate and highly orchestrated sequence of events during development and aging, causing alterations that can lead to cell dysfunction and disease. Internal and external sources of DNA damage constantly bombard the genome. Examples of external sources include ultraviolet radiation and exposure to chemical agents, while internal sources include cell processes that can arise, for example, from the reactive byproducts of metabolism. Fortunately, nature has evolved a special group of proteins known as DNA damage and repair proteins that act as surveyors to detect erroneous messages. These specialized proteins ensure that damage to the DNA molecules that encode our genetic information is not passed to the new generation of cells during cell division or during the expression of our genes, ultimately protecting our genome. Many genetic disorders are caused by mutations in the genetic material. This leads to a dysfunctional RNA or protein with little or no function (loss of function) or an RNA or protein with an entirely new function (gain of function). Since DNA repair proteins play a crucial role in identifying and targeting mistakes made in the message, it stands to reason that impairment in the DNA repair process might lead to disease. In this study, Rui Gao and colleagues through an extensive collaboration sought to understand the connection between altered DNA repair and Huntington’s disease.

Blue strands of DNA
An artist’s rendering of DNA molecules.

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