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The Sheffield culture guide written by in-the-know locals

DNA Repair to the Rescue

El-Khamisy research group website: https://www.sheffield.ac.uk/mbb/staff/sherifelkhamisy
Twitter: @sek2016t

Our DNA is constantly exposed to different sources of stress. Some of these happen from normal processes in our cells, while others are caused by external factors. Thankfully, our cells have a fantastic repair system that can detect and repair our damaged DNA. However, in some cases something goes wrong and the consequences of accumulated DNA damage are ageing, cancer and neurodegeneration.

In the El-Khamisy Research Group, we focus on the study of DNA damage, and the things that occur when the repair system fails. For our research, we use human primary cells as well as cancerous and modified cell lines. For the study of the brain specifically, the challenge is the lack of access to human brain cells; therefore, in the lab this is resolved by reprogramming and differentiating skin cells, to form brain cells (neurons).

Some of the cells we work with. From left to right: lung fibroblasts stained for nucleoli (green) and R-loops (red); skin fibroblasts overexpressing GFP; GABAergic neurons stained for neuronal markers DARP32 (red), TUJ1 (green) and the nuclear stain DAPI (blue)

What is DNA and how can it get damaged?
Activity suitable for ages 10+

DNA is the ‘recipe’ that contains all the information needed for a living organism to look and function properly. It is present in every cell, specifically, in the nucleus.

Our DNA is a double-helical molecule that is composed of smaller building blocks called nucleotides. The outside of the double helix is a phosphate backbone. The inside contains bases such as Adenine (A), Guanine (G), Cytosine (C) and Thymine (T) that pair specifically with each other. Adenine pairs with Thymine, while Guanine pairs with Cytosine, fitting together just like pieces of a jigsaw puzzle.

Our DNA is constantly exposed to different sources that may cause it to be damaged. These can be internal sources, what we call as endogenous sources, or they can be external sources, which we refer to as exogenous sources.

Examples of endogenous sources include:

  1. DNA replication - the process by which our cells make new copies of the DNA.
  2. Formation of reactive oxygen species (ROS) in the mitochondria

Examples of exogenous sources include:

  1. Ultraviolet (UV) rays from sunlight
  2. Radiation
  3. Chemicals or drugs
  4. Smoking

Click on the link below to play a game to test your knowledge about the different sources of DNA damage. Match the image (click on the blue circle below it) to the source of damage described at the top (text above box between scoring and timer).

How can our DNA be damaged game

Types of DNA damage lesions
Activity suitable for ages 10+

It is important that our cells maintain a ‘healthy’ and ‘intact' DNA as it is required for normal functioning of the cells. The different sources of DNA damage, can result in the formation of different types of lesions. These include:

1. Single Strand Breaks - this means that one of the two strands of the DNA is broken, forming a nick or a gap

2. Double Strand Breaks - unrepaired single strand breaks can sometimes form double strand breaks, which are very dangerous to the cells

3. Deletions - some nucleotides are removed from the DNA sequence

4. Insertions - new nucleotides are inserted in the DNA sequence

5. Mutations - one of the bases can be replaced with a different one, which would not allow the correct base pairing to happen

Click on the link below to play a game to test your knowledge about the different types of lesions that can happen to our DNA when it is exposed to a DNA damaging agent. Match the image (click on the blue circle below it) to the source of damage described at the top (text above box between scoring and timer).

What happens when our DNA is exposed to a damaging agent game

R-loops as a source of DNA damage
One of our research focuses is the impact caused by R-loops on the DNA. These structures have been associated with neurodegeneration and cancer. Open our R-loops presentation (PDF) to find out more.

Word search puzzle
Activity suitable for ages 10+

Have fun trying to find words related to R-loops on the puzzle below

How do our cells respond to damaged DNA?
Activity suitable for ages 10+

Once DNA is damaged, our DNA repair process is initiated in the cells. It is the process by which our cells recognize the regions in our DNA that have been damaged, in order to correct this damage. Several players are recruited as part of the multi-step process, which is briefly described below:

  1. DNA damage sensors recognize the breaks in the DNA
  2. Nucleases (enzymes that can cut through the DNA strand), act as molecular scissors to excise the damaged lesion
  3. DNA Polymerase, fills in the gaps formed by the nucleases with nucleotides, which are complementary to the opposite strand
  4. DNA Ligases, then seal the nicks formed between the new nucleotides and the older DNA strand, so that they are joined together
  5. The DNA is repaired and the cell is now ‘healthy’ and able to function normally

Click on the link below to play a game to test your knowledge about how cells respond when they are exposed to a DNA damaging agent. Match the image (click on the blue circle below it) to the player in the process described at the top (text above box between scoring and timer).

How do our cells respond to damaged DNA game 



What happens in our cells when our DNA cannot be repaired?

Activity suitable for ages 10+

While we’re usually fortunate to have a fantastic repair system that can recognise and repair the damaged DNA lesions, sometimes, it fails to do so. This can be due to a defect in any of the repair players, making them unable to perform their function. As a result, there could be several consequences, which include:
1. Cancer - it is the uncontrolled cell division. When our repair system fails and mutations are introduced, cancer development becomes one of the most prominent consequences. 

2. Neurodegenerative disorders - these are disorders that happen in brains such as Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis (ALS)

3. Senescence - this means that cells stop dividing, yet they are still ‘alive’, so we refer to them as dormant cells 

4. Ageing - it is a physiological process i.e. it happens normally to our bodies and is a consequence of unrepaired DNA 

5. Apoptosis - it is programmed cell death i.e. cells ‘kill’ themselves when they are unable to repair their DNA and hence unable to function normally anymore”

Click on the link below to play a game to test your knowledge about the consequences that can take place in case our cells fail to repair the damaged DNA. Match the image (click on the blue circle below it) to the word at the top (text above box between scoring and timer).

What happens when damaged DNA is unrepaired game

Neurodegeneration
Activity suitable for ages 10+

The brain is one of the most powerful organs in the body. It is able to control most activities in the body. The brain cells are called neurons and they communicate with each other, as well as other organs to transmit information by electrical and chemical impulses. The neurons cannot divide to generate new cells, so when the brain is damaged there is neuronal loss in a process called neurodegeneration. Neurodegeneration can be caused by a variety of factors, including failing to repair DNA damage.

Open our Neurodegeneration presentation (PDF) to find out more.

Brain Jigsaw Puzzle
Complete this Brain Jigsaw Puzzle.

How can we protect our DNA from being damaged?
Activity suitable for ages 10+

In our day to day life, we are exposed to different sources of stress that can damage our DNA and our repair system works to repair them efficiently as they’re formed. It is in our hands to further support our DNA repair system, by keeping our body, and therefore, our cells healthy.

  1. Eating anti-oxidant rich food, to protect us from the excess reactive oxygen species
  2. Stress management techniques such as meditation and mindfulness exercises
  3. Avoid smoking due to the presence of chemicals that damage the DNA and lead to cancer
  4. Avoid excess exposure to sunlight to minimize our exposure to the damaging UV rays
  5. Regular exercise to ensure our body is fit and healthy

Click on the link below to play a game to test your knowledge about how you can protect your DNA repair system, to keep your DNA intact. Match the image (click on the blue circle below it) to the phrase at the top (text above box between scoring and timer).

How can we protect our DNA from being damaged game

Group activities
Activity suitable for ages 10+

Refresh on the topics covered above through a memory card game. You can choose to play online or download a printable version of your preferred size and enjoy playing it with your family and friends.

DNA Repair Matching
DNA Repair Matching Cards game

R-loop UNO card game
Keep playing and learning at home with this R-loop UNO card downloadable game (PDF). Print one sided on A4 paper for best results.

Ask Professor Sherif El-Khamisy and his research group colleagues about DNA damage and repair.

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The answers to your questions will be available here on Friday 5 June 2020.

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