What happens when your DNA is damaged? - Monica Menesini

Summary

The video explains how DNA in our cells experiences constant damage, with up to a quintillion errors occurring daily across the body. DNA repair mechanisms, involving specialized enzymes, correct these errors through processes like mismatch repair, base excision repair, and nucleotide excision repair. While most damage is fixed, severe issues like double-strand breaks can lead to serious conditions, including cancer. These repair pathways are vital for maintaining genetic stability, preventing premature aging, and protecting against diseases. Although mutations can sometimes be beneficial for evolution, the body's goal is to preserve DNA integrity.

Takeaways

• 🧬 The DNA in a single cell can be damaged tens of thousands of times per day, and when multiplied by the body's trillions of cells, this amounts to a quintillion DNA errors daily.
• ⚠️ DNA damage can cause serious issues, including cancer, as it disrupts the blueprint for the proteins cells need to function properly.
• 🧱 Errors in DNA can take various forms, such as damaged nucleotides, incorrect base pairing (mutations), and nicks in DNA strands that can affect replication.
• 🔧 Cells have multiple repair pathways to address different types of DNA damage, using specialized enzymes for each repair process.
• 🔍 One common error, base mismatches during replication, is corrected by DNA polymerase and additional proteins in a process called mismatch repair, reducing errors to about one in a billion.
• 🛡️ DNA can also be damaged after replication due to environmental factors like tobacco smoke or natural cellular molecules like hydrogen peroxide.
• ✂️ Base excision repair is used to fix single damaged bases, while nucleotide excision repair addresses more complex damage, such as UV-induced DNA distortions.
• 🌟 High-frequency radiation, like gamma and x-rays, can cause dangerous double-strand breaks in DNA, which are repaired by homologous recombination or non-homologous end joining.
• 🔄 Homologous recombination uses an undamaged DNA template for accurate repair, while non-homologous end joining directly fuses broken DNA ends but with less precision.
• ⏳ Defects in DNA repair are linked to premature aging and cancer, making efficient DNA repair systems crucial for maintaining cellular health and stability.

Q & A

What causes DNA damage in cells?

DNA damage can be caused by environmental factors like UV light and chemicals in tobacco smoke, as well as natural cellular processes involving molecules such as hydrogen peroxide.

How often does DNA polymerase make a mistake during replication?

DNA polymerase makes a mistake about once every 100,000 nucleotide additions.

What is mismatch repair, and why is it important?

Mismatch repair is a system where proteins correct base pairing errors after DNA replication. It reduces base mismatch errors to about one in one billion, ensuring the integrity of the genetic code.

What is the difference between base excision repair and nucleotide excision repair?

Base excision repair fixes single damaged bases, while nucleotide excision repair handles more complex damage, like UV-induced distortions where adjacent nucleotides stick together.

How do homologous recombination and non-homologous end joining differ in repairing double-strand breaks?

Homologous recombination uses an undamaged DNA template to repair the break, while non-homologous end joining trims the ends and fuses them without a template, which can lead to gene mix-ups.

What are the dangers of double-strand DNA breaks?

Double-strand breaks are the most dangerous type of DNA damage, and even one break can cause cell death if not properly repaired.

Why are DNA repair mechanisms so crucial to health?

DNA repair mechanisms prevent mutations that can lead to serious problems like cancer and premature aging, ensuring the stability of the genome.

What type of DNA damage does UV light cause?

UV light can cause adjacent nucleotides to stick together, distorting the DNA double helix, which requires repair by the nucleotide excision repair process.

What are beneficial mutations, and how do they relate to DNA damage?

Beneficial mutations are changes in DNA that can improve an organism's ability to survive, driving evolution. While most DNA changes are harmful, some are advantageous.

How are DNA repair defects linked to aging and cancer?

Defects in DNA repair mechanisms are associated with accelerated aging and various forms of cancer, as damaged DNA accumulates in cells and disrupts normal functioning.

Outlines

00:00

🧬 DNA Damage and Repair: The Daily Challenge

The DNA in each of our cells undergoes tens of thousands of damages every day, and when multiplied by the number of cells in the human body, it totals an enormous amount of potential DNA errors daily. DNA damage is serious as it provides the blueprint for vital proteins. Various types of damage, such as nucleotide mismatches or strand nicks, can lead to diseases like cancer. Fortunately, cells are equipped with repair mechanisms to address most errors, ensuring the stability of DNA and cellular functions.

🔄 DNA Mismatches and the Repair System

One of the most common types of DNA errors occurs when nucleotides are mismatched during replication. DNA polymerase, the enzyme responsible for replication, pairs nucleotides like adenine with thymine and guanine with cytosine, but errors happen about once in every hundred thousand additions. To mitigate this, DNA polymerase corrects most mistakes immediately, and a backup system known as mismatch repair steps in if any mismatches are missed. Together, these systems drastically reduce errors, lowering the mismatch rate to about one in a billion nucleotides.

⚛️ Chemical Damage: Internal and Environmental Threats

DNA damage isn’t limited to replication errors; it can also be chemically altered by external factors, such as tobacco smoke, or internal molecules, like hydrogen peroxide. Cells combat these with enzymes that reverse specific chemical changes. General repair pathways also exist to fix damage post-replication, including base excision repair, where damaged nucleotides are snipped out and replaced by specialized enzymes. This highlights the cell's resilience against both internal and external chemical threats to DNA integrity.

☀️ UV Damage and the Complex Nucleotide Excision Repair

UV light can cause adjacent nucleotides in DNA to bond, distorting the double helix. Repairing this requires nucleotide excision repair, a more elaborate process than base excision. In this system, a group of proteins removes a long strand of about 24 nucleotides, replacing them to restore the DNA's original shape and function. This process is crucial for maintaining DNA stability after UV exposure, which can distort the structure significantly.

⚡ Radiation and the Perils of Double-Strand Breaks

High-frequency radiation, such as gamma rays or X-rays, can cause severe DNA damage by breaking one or both strands of the DNA backbone. Double-strand breaks are particularly dangerous and can lead to cell death. Cells have two primary pathways to fix these breaks: homologous recombination, which uses an undamaged DNA template to restore the broken strand, and non-homologous end joining, which directly fuses the broken ends but is less accurate. Both methods are essential for survival, but errors in repair can lead to genetic instability.

🔄 DNA Repair: Evolution and Health

While changes in DNA can occasionally lead to beneficial mutations and drive evolution, most mutations are harmful. DNA repair mechanisms work constantly to maintain genetic stability, and failures in these systems are linked to cancer and premature aging. These repair processes are a natural defense, working billions of times a day to preserve the integrity of DNA and ensure healthy cellular function.

Keywords

💡DNA damage

DNA damage refers to alterations in the DNA structure, which can happen tens of thousands of times per day in a single cell. The video explains that this damage is caused by environmental factors, like UV light or tobacco smoke, or by natural cellular processes. If left unrepaired, DNA damage can lead to mutations, cancer, and other serious health issues.

💡Nucleotide

Nucleotides are the building blocks of DNA, consisting of a sugar, a phosphate, and a base. DNA replication relies on matching nucleotides correctly, where adenine pairs with thymine, and guanine with cytosine. Errors in nucleotide pairing, known as base mismatches, are corrected through specialized repair mechanisms like mismatch repair.

💡Mismatch repair

Mismatch repair is a cellular process that fixes errors in DNA replication, particularly when nucleotides are incorrectly paired. If the DNA polymerase enzyme makes an error, a set of proteins detects and removes the incorrect nucleotide and replaces it with the correct one. This repair process reduces the error rate to approximately one in a billion.

💡Base excision repair

Base excision repair is a repair mechanism used when a single nucleotide base is damaged, such as by oxidative stress from hydrogen peroxide. This process involves cutting out the damaged base and replacing it with a correct one. It helps maintain the integrity of the DNA by preventing small lesions from becoming larger problems.

💡Nucleotide excision repair

Nucleotide excision repair is a more complex repair process that fixes damage affecting a larger section of DNA, such as when UV light causes two adjacent nucleotides to stick together. This process involves removing a strand of 24 or so nucleotides and replacing it with new ones to restore the DNA's correct shape and function.

💡Homologous recombination

Homologous recombination is one of the main pathways used to repair double-strand breaks in DNA. It involves using an undamaged section of DNA as a template to guide the repair, ensuring a more accurate reconstruction of the damaged area. This process is critical for maintaining genetic stability after severe DNA damage.

💡Non-homologous end joining

Non-homologous end joining is another pathway for repairing double-strand breaks, but unlike homologous recombination, it doesn't rely on a template. Instead, the broken ends are trimmed and fused together, which can lead to small errors or mutations. This method is less accurate but useful when the cell doesn't have a matching template available.

💡Double-strand breaks

Double-strand breaks occur when both strands of the DNA helix are severed, typically due to exposure to high-frequency radiation like x-rays or gamma rays. These breaks are particularly dangerous because they can lead to cell death or genomic instability. Repair pathways like homologous recombination and non-homologous end joining address this type of damage.

💡Mutations

Mutations are changes in the DNA sequence that can result from errors in replication or unrepaired DNA damage. Some mutations are harmless, while others can cause serious problems, such as cancer. The video mentions that mutations can sometimes be beneficial, leading to evolutionary advantages, but most DNA changes are undesirable.

💡DNA repair enzymes

DNA repair enzymes are specialized proteins responsible for identifying and correcting different types of DNA damage. Each enzyme targets a specific kind of error, whether it's a base mismatch or a double-strand break. These enzymes are crucial for maintaining the stability of genetic information and preventing diseases like cancer.

Highlights

The DNA in just one of your cells gets damaged tens of thousands of times per day.

Your body has about a hundred trillion cells, resulting in a quintillion DNA errors every day.

DNA errors can cause serious problems such as cancer because DNA provides the blueprint for proteins essential for cell function.

DNA errors occur in various forms, including damaged nucleotides, incorrect base pairings, mutations, and nicks in the DNA strand.

Cells have repair pathways that use specialized enzymes to fix most DNA damage most of the time.

Mismatch repair reduces base mismatch errors to about one in a billion after DNA polymerase mistakes during replication.

Base excision repair is used to fix single damaged bases in DNA.

Nucleotide excision repair is a more complex process used to fix damage caused by UV light, which distorts the DNA helix.

Gamma rays and x-rays can cause double-strand breaks, the most dangerous form of DNA damage, which can result in cell death.

Homologous recombination and non-homologous end joining are two main pathways to repair double-strand breaks in DNA.

Homologous recombination uses a similar undamaged DNA strand as a template to repair breaks accurately.

Non-homologous end joining fuses broken DNA ends together without a template, which can be less accurate and cause gene rearrangements.

Beneficial mutations can lead to evolutionary adaptations, though most DNA changes are harmful.

Defects in DNA repair are linked to premature aging and various forms of cancer.

The DNA repair mechanisms in your cells operate billions of times a day to maintain genomic stability.

Transcripts

The DNA in just one of your cells

gets damaged tens of thousands of times per day.

Multiply that by your body's hundred trillion or so cells,

and you've got a quintillion DNA errors everyday.

And because DNA provides the blueprint

for the proteins your cells need to function,

damage causes serious problems, such as cancer.

The errors come in different forms.

Sometimes nucleotides, DNA's building blocks, get damaged,

other times nucleotides get matched up incorrectly,

causing mutations,

and nicks in one or both strands can interfere with DNA replication,

or even cause sections of DNA to get mixed up.

Fortunately, your cells have ways of fixing most of these problems

most of the time.

These repair pathways all rely on specialized enzymes.

Different ones respond to different types of damage.

One common error is base mismatches.

Each nucleotide contains a base,

and during DNA replication,

the enzyme DNA polymerase is supposed to bring in the right partner

to pair with every base on each template strand.

Adenine with thymine, and guanine with cytosine.

But about once every hundred thousand additions,

it makes a mistake.

The enzyme catches most of these right away,

and cuts off a few nucleotides and replaces them with the correct ones.

And just in case it missed a few,

a second set of proteins comes behind it to check.

If they find a mismatch,

they cut out the incorrect nucleotide and replace it.

This is called mismatch repair.

Together, these two systems reduce the number of base mismatch errors

to about one in one billion.

But DNA can get damaged after replication, too.

Lots of different molecules can cause chemical changes to nucleotides.

Some of these come from environmental exposure,

like certain compounds in tobacco smoke.

But others are molecules that are found in cells naturally,

like hydrogen peroxide.

Certain chemical changes are so common

that they have specific enzymes assigned to reverse the damage.

But the cell also has more general repair pathways.

If just one base is damaged,

it can usually be fixed by a process called base excision repair.

One enzyme snips out the damaged base,

and other enzymes come in to trim around the site and replace the nucleotides.

UV light can cause damage that's a little harder to fix.

Sometimes, it causes two adjacent nucleotides to stick together,

distorting the DNA's double helix shape.

Damage like this requires a more complex process

called nucleotide excision repair.

A team of proteins removes a long strand of 24 or so nucleotides,

and replaces them with fresh ones.

Very high frequency radiation, like gamma rays and x-rays,

cause a different kind of damage.

They can actually sever one or both strands of the DNA backbone.

Double strand breaks are the most dangerous.

Even one can cause cell death.

The two most common pathways for repairing double strand breaks

are called homologous recombination and non-homologous end joining.

Homologous recombination uses an undamaged section of similar DNA as a template.

Enzymes interlace the damaged and undamgaed strands,

get them to exchange sequences of nucleotides,

and finally fill in the missing gaps

to end up with two complete double-stranded segments.

Non-homologous end joining, on the other hand,

doesn't rely on a template.

Instead, a series of proteins trims off a few nucleotides

and then fuses the broken ends back together.

This process isn't as accurate.

It can cause genes to get mixed up, or moved around.

But it's useful when sister DNA isn't available.

Of course, changes to DNA aren't always bad.

Beneficial mutations can allow a species to evolve.

But most of the time, we want DNA to stay the same.

Defects in DNA repair are associated with premature aging

and many kinds of cancer.

So if you're looking for a fountain of youth,

it's already operating in your cells,

billions and billions of times a day.