DNA Repair

Summary

DNA repair is a vital cellular process that identifies and corrects DNA damage from both internal and external sources, which can occur up to a million times per cell daily. The script explains how cells detect alterations in the DNA helix and initiate repair through various mechanisms, including nucleotide excision, base excision, mismatch repair, and double-strand repair methods like non-homologous end joining and homologous recombination. It highlights the importance of these processes in preventing diseases such as melanoma and the potential consequences of repair failure, including senescence, apoptosis, and cancer.

Takeaways

• 🧬 DNA repair is a set of processes that identify and correct damage to the DNA molecules in a cell's genome.
• 🔍 Damage to DNA can originate from two sources: endogenous (internal, like normal metabolic activities) and exogenous (external, such as environmental factors).
• 🔢 Human cells may experience up to one million incidents of DNA damage per cell per day, highlighting the constant activity of DNA repair mechanisms.
• 🔍🧬 DNA damage is recognized by alterations in the spatial configuration of the DNA helix, which cells can detect.
• 🛠️ DNA repair mechanisms are categorized into single strand and double strand repair, each with specific methods depending on the type of damage.
• ☀️ UV light exposure can cause pyrimidine dimers, which are repaired by nucleotide excision repair involving specific enzymes and DNA polymerase.
• 🧪 Base excision repair is utilized when damage to a particular DNA base occurs, such as deamination induced by chemicals like nitrates.
• 🔄 Mismatch repair corrects errors that occur during DNA replication and recombination, involving mis-paired nucleotides.
• 🧬🔗 Double strand repair mechanisms include non-homologous end joining, microhomology-mediated end joining, and homologous recombination, each dealing with breaks in both DNA strands.
• 🧬🔧 Homologous recombination uses a sister chromatid or homologous chromosome as a template for repair, involving enzymatic machinery similar to chromosomal crossover during myosis.
• 🛑 Cells with accumulated DNA damage or ineffective repair mechanisms may enter senescence, undergo apoptosis, or lead to unregulated cell division potentially forming tumors.

Q & A

What is DNA repair?

DNA repair is a set of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

What are the two main sources of DNA damage mentioned in the script?

The two main sources of DNA damage are endogenous (internal) sources from normal metabolic activities within a cell, and exogenous (external) sources from environmental factors.

How many incidences of DNA damage can occur per cell per day?

Together, the two sources of damage can result in as many as one million incidences of DNA damage per cell per day.

How is DNA damage recognized by the cell?

Damage to DNA alters the spatial configuration of the helix, which can be detected by the cell, such as a bulge in the DNA double helix.

What are the two main types of DNA repair mechanisms?

The two main types of DNA repair mechanisms are single strand repair mechanisms and double strand repair mechanisms.

What are the three main types of single strand repair mechanisms?

The three main types of single strand repair mechanisms are nucleotide excision repair, base excision repair, and mismatch repair.

How does nucleotide excision repair work?

Nucleotide excision repair involves specific enzymes called endonucleases cutting out the damaged nucleotides, DNA polymerase replacing the bases, and DNA ligase resealing the gap.

What is the consequence of nucleotide excision repair failure in the context of UV light exposure?

Failure of nucleotide excision repair to fix damage caused by UV light can lead to melanoma, a form of skin cancer.

How does base excision repair address DNA damage?

Base excision repair uses specific glycosylases to recognize and remove the damaged base, followed by endonuclease cutting the phosphodiester backbone, and then DNA polymerase filling the gap and ligase resealing it.

What is mismatch repair and why is it important?

Mismatch repair corrects errors that occur in DNA replication and recombination, leading to mis-paired but not necessarily damaged nucleotides, ensuring the fidelity of genetic information.

What are the three main mechanisms of double-strand repair?

The three main mechanisms of double-strand repair are non-homologous end joining, microhomology-mediated end joining, and homologous recombination.

How does non-homologous end joining differ from other double-strand repair mechanisms?

Non-homologous end joining directly joins the two ends of a break without the need for a homologous template, using a specialized DNA ligase and a co-factor.

What role does homologous recombination play in double-strand repair?

Homologous recombination requires the presence of an identical or nearly-identical sequence to be used as a template for the repair of the break, often using a sister chromatid or a homologous chromosome.

What are the possible outcomes for a cell that has accumulated a large amount of DNA damage or can no longer effectively repair its DNA?

A cell with accumulated DNA damage or ineffective repair mechanisms can enter senescence (a state of dormancy), undergo apoptosis (programmed cell death), or experience unregulated cell division leading to tumor formation and potentially cancer.

Outlines

00:00

🧬 DNA Repair Mechanisms and Their Importance

DNA repair is a vital cellular process that identifies and corrects damage to the DNA molecules within a cell's genome. Damage can originate from endogenous sources like normal metabolic activities or exogenous sources such as environmental factors, leading to up to one million incidents of damage per cell daily. The cell detects alterations in the DNA helix's spatial configuration, triggering DNA repair molecules to bind at the site of damage. Repair mechanisms are categorized into single and double strand repair, with nucleotide excision repair, base excision repair, and mismatch repair being the primary single strand methods. These methods are chosen based on the type of damage, such as UV-induced pyrimidine dimers or base damage from chemicals. Melanoma, a skin cancer, can result from the failure of nucleotide excision repair. Mismatch repair corrects errors in DNA replication and recombination. Double strand repair mechanisms include non-homologous end joining, microhomology-mediated end joining, and homologous recombination, which are crucial for repairing breaks in both DNA strands caused by ionizing radiation.

05:01

🔬 Consequences of Ineffective DNA Repair

The rate of DNA repair is influenced by various factors, including cell type, cell age, and the extracellular environment. When a cell accumulates significant DNA damage or loses its ability to repair effectively, it may enter one of three states: senescence, a dormant state akin to hibernation; apoptosis, a programmed cell death process; or unregulated cell division, which can potentially lead to tumor formation and cancer. Homologous recombination, one of the double strand repair mechanisms, uses a sister chromatid or homologous chromosome as a template for repair, involving enzymatic machinery similar to that in chromosomal crossover during myosis. Understanding these repair mechanisms is crucial for grasping the cell's response to DNA damage and its implications for health and disease.

Keywords

💡DNA repair

DNA repair refers to the biological processes that cells use to identify and correct damage to the DNA molecules that constitute the cell's genome. It is central to the video's theme as it explains how cells maintain genetic integrity. The script mentions that DNA repair is constantly active due to the potential for up to one million incidences of damage per cell per day.

💡Endogenous sources

Endogenous sources of DNA damage are those that originate from within the cell, such as from normal metabolic activities. This concept is important in understanding the video's theme as it highlights the inherent risks to DNA integrity that come from the cell's own functioning, as opposed to external factors.

💡Exogenous sources

Exogenous sources are external factors that can cause DNA damage, such as environmental elements. The video emphasizes that these sources, along with endogenous ones, contribute to the frequent need for DNA repair mechanisms to be activated.

💡DNA helix

The DNA helix is the structural form of DNA, resembling a twisted ladder. The video script uses the alteration of the DNA helix's spatial configuration as an example of how damage can be detected by the cell, illustrating the importance of the helix's structure in DNA repair.

💡Nucleotide excision repair

Nucleotide excision repair is a specific DNA repair mechanism that corrects damage caused by UV light, such as pyrimidine dimers. The video explains this process as an example of how cells deal with certain types of DNA damage, emphasizing its role in preventing skin cancer like melanoma.

💡Base excision repair

Base excision repair is another DNA repair mechanism that targets damage to specific bases within the DNA strand, such as deamination caused by chemicals like nitrates. The script describes this process to illustrate how cells correct base-level damage.

💡Mismatch repair

Mismatch repair corrects errors that occur during DNA replication and recombination, which result in mis-paired nucleotides. The video uses this concept to explain how cells ensure the accuracy of genetic information passed on through cell division.

💡Double strand repair

Double strand repair mechanisms address damage that occurs to both strands of the DNA helix, often due to ionizing radiation. The video script outlines three main types of double strand repair, emphasizing the complexity of DNA repair processes in response to severe damage.

💡Non-homologous end joining

Non-homologous end joining is a double strand repair mechanism that directly ligates broken DNA ends without the need for a homologous template. The video script explains this as one of the ways cells can rapidly repair double-strand breaks.

💡Microhomology-mediated end joining

Microhomology-mediated end joining is another double strand repair mechanism that uses short regions of homology to align and ligate broken DNA ends. The script describes this process to illustrate a more precise method of repairing double-strand breaks.

💡Homologous recombination

Homologous recombination is a double strand repair mechanism that uses an identical or nearly identical sequence as a template for repair. The video script relates this process to the chromosomal crossover during myosis, highlighting its role in accurate DNA repair.

💡Senescence

Senescence is an irreversible state of dormancy that a cell can enter when it has accumulated a large amount of DNA damage. The video script uses this term to describe one of the possible outcomes for cells that can no longer effectively repair DNA damage.

💡Apoptosis

Apoptosis, or programmed cell death, is another potential outcome for cells with extensive DNA damage. The video script mentions this term to explain a cell's self-destruction as a response to irreparable DNA damage.

💡Unregulated cell division

Unregulated cell division can lead to the formation of tumors that may become cancerous. The video script uses this term to describe the final possible outcome for cells that have sustained too much DNA damage and can no longer repair it effectively.

Highlights

DNA repair is a critical process by which a cell identifies and corrects damage to its genome.

There are two main sources of DNA damage: endogenous from normal metabolic activities and exogenous from environmental factors.

Human cells can experience up to one million incidences of DNA damage per day.

DNA damage alters the spatial configuration of the DNA helix, which can be detected by the cell.

DNA repair mechanisms are categorized into single strand and double strand repair methods.

Three main types of single strand repair mechanisms are nucleotide excision repair, basic excision repair, and mismatch repair.

UV light exposure can cause pyrimidine dimers, which are repaired by nucleotide excision repair.

Melanoma, a form of skin cancer, can result from the failure of nucleotide excision repair to fix UV-induced damage.

Base excision repair is responsible for fixing damage to a particular base within a DNA strand.

Deamination of a DNA base can be corrected by base excision repair involving glycosylases and endonucleases.

Mismatch repair corrects errors in DNA replication and recombination that lead to mis-paired nucleotides.

In bacteria, transient methylation helps distinguish the newly-synthesized strand with errors from the correct parental strand.

Double strand repair mechanisms include non-homologous end joining, microhomology-mediated end joining, and homologous recombination.

Non-homologous end joining directly ligates the broken ends of DNA without the need for a homologous template.

Microhomology-mediated end joining aligns strands based on short homologous sequences and fills in missing base pairs.

Homologous recombination uses a sister chromatid or homologous chromosome as a template for repair.

The rate of DNA repair depends on factors such as cell type, cell age, and the extracellular environment.

Cells with accumulated DNA damage or ineffective repair mechanisms may enter senescence, apoptosis, or unregulated cell division leading to cancer.

Transcripts

- [Narrator] What is DNA repair?

DNA repair is a collection of processes

by which a cell identifies and corrects damage

to the DNA molecules that encode its genome.

Now in human cells, damage can occur from sort of

one of two different types of sources,

the first being endogenous, or internal sources,

and these can come from the normal metabolic activities

that occur within a cell.

The second type of source of damage

is from exogenous, or external sources,

and these can be any one

of a number of environmental factors.

Now together, these two sources can result

in as many as one million incidences

of damage per cell, per day.

And so, the DNA repair process is constantly active

as a response to damage in the structure of DNA.

So how is damage to the DNA recognized in the first place?

Well, damage to DNA alters

the actual spatial configuration of the helix.

And such alterations can be detected by the cell.

So as you can see here, there's a little bulge

in the DNA double helix, and that can be detected.

So once the damage is localized,

this triggers specific DNA repair molecules

to bind at, or near, the site of damage,

and enable the repair to take place.

Now, DNA repair mechanisms can be separated

into single strand repair mechanisms,

and double strand repair mechanisms.

And there are three main types

of single strand repair mechanisms.

And those are nucleotide excision repair,

basic excision repair, and then mismatch repair.

And the method of repair that gets employed

really depends on the type of damage

that gets incurred by the strand of DNA.

Now, if the strand of DNA is exposed to UV light,

a photochemical reaction induces the formation

of these covalent linkages between adjacent pyrimidines

such as thymine or cytosine, those are the pyrimidine bases.

And this yields pyrimidine dimers,

which is actually the example of the damage shown here

in the upper right corner of the screen.

Now, these pyrimidine dimers are recognized

by specific enzymes called endonucleases

that cut out the damaged nucleotides.

Hence nucleotide excision repair,

because the entire nucleotide is excised, or cut out.

Then, DNA polymerase replaces the bases

and DNA ligase reseals the gap.

Now not surprisingly, melanoma,

which is a form of skin cancer,

can occur if nucleotide excision repair

fails to fix the damage caused by UV light.

Now, if there is damage to a particular base,

then base excision repair comes into play.

Certain chemicals like nitrates, for example,

can lead to deamination of a base within a strand of DNA.

And deamination is simply the removal of an amino group.

Now when this occurs,

base excision repair uses specific glycosylases

to recognize and remove the damaged space.

And endonuclease then cuts the phosphodiester backbone

that is left behind at the damaged site,

and then the gap is filled by DNA polymerase

and then resealed by ligase.

And finally, the last single strand repair mechanism

is mismatch repair, which corrects the errors that occur

in DNA replication and recombination

that lead to mis-paired,

but not necessarily damaged nucleotides.

Now in bacteria, transient methylation distinguishes

the newly-synthesized daughter strand

with the error from the correct parental strand,

which ensures that the repair occurs

according to the correct template.

In eukaryotes, the exact mechanism

is not quite elucidated yet.

So, those are the main types of single strand repair.

Now, let's talk about double strand repair.

Damage that occurs to both strands in the double helix

can occur when there is exposure to ionizing radiation

such as gamma rays and x-rays.

And just like there are three main mechanisms

for single-strand repair,

there are three main mechanisms of double-strand repair.

And they are non-homologous end joining,

microhomology-mediated end joining,

and homologous recombination.

Now, in non-homologous end joining,

a specialized DNA ligase forms a complex

with a co-factor that directly joins the two ends,

and the break ends are directly ligated

without the need for homologous template.

Now, when I say homologous,

I'm referring to a similar linear sequence of gene loci.

And the same goes for whenever I use the word homology.

It's any two DNA sequences that have similar gene loci.

Now, microhomology-mediated end joining

works by ligating the mismatched hanging strands of a DNA,

removing the overhanging nucleotides,

and then filling in the missing base pairs.

So when a break occurs, a homology of, say,

5 to 25 complimentary base pairs

on both strands is identified,

and then used as a basis for which to align the strands

with the mismatched ends.

Once aligned, any overhanging bases, or flaps,

and mismatched bases on the strands are removed,

and any missing nucleotides are inserted.

Now finally, homologous recombination requires the presence

of identical, or nearly-identical sequence to be used

as a template for the repair of the break.

And this pathway allows a damaged chromosome to be repaired

using a sister chromatid,

or a homologous chromosome as a template.

The enzymatic machinery that's responsible

for this repair process is nearly identical

to the machinery responsible for a chromosomal crossover

that occurs during myosis.

And so that is it for double stranded repair mechanisms.

Now, the actual rate of DNA repair

is dependent on a lot of factors including the cell type,

the age of the cell, and the extracellular environment

just to name a few.

And a cell that has accumulated a large amount of DNA damage

or one that can no longer effectively repair

the damage incurred to its DNA,

can enter one of three possible states.

Now, the first one is an irreversible state of dormancy

known as senescence.

And you can kind of think of the cell in this case

as kind of going into a hibernating mode.

And the second possible state is known as apoptosis,

or programed cell death.

And then the third possible outcome

is unregulated cell division,

which can lead to the formation of a tumor

that can become cancerous.