Name: dna mismatch repair and cancer risk
Uploaded: 2023-04-30T11:44:41.000Z
Duration: 1 min 20 s
Channel: JoVE

K12 Standards

north-carolina-k-12-science-standard-course-of-study

NC K-12 Science Standard Course of Study

9-12

Biology

heredity-inheritance-and-variation-of-traits

Heredity- Inheritance and Variation of Traits

LS.Bio.6.2

Mismatch Repair

Mismatched base pairs, such as adenine with cytosine, can sometimes escape proofreading during replication and are later fixed through the process of mismatch repair.
In E. coli, the mismatch recognition protein, MutS, identifies mismatched bases due to their abnormal structure.
It then recruits MutL and forms the MutS-MutL complex. This activated complex stimulates MutH, an endonuclease, to nick the newly synthesized strand.
Genomic DNA in E. coli usually has methyl groups attached at specific sites. However, there is a certain time delay before a newly synthesized strand is methylated.
This allows the repair complex to identify the new strand based on its methylation status, and MutH nicks it at the nearest unmethylated site, while the template strand remains unchanged.
A helicase unwinds the cleaved DNA segment from the template strand. An exonuclease hydrolyses the erroneous region, thus, leaving a gap in the new strand.
Finally, DNA polymerase fills the gap with the correct nucleotides, and DNA ligase seals the nick, repairing the error.

mismatch repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic information needs to be replicated. Despite the proofreading ability of the DNA polymerase, a copying error occurs approximately every 1 million base pairs. One type of error is the mismatch of nucleotides, for example, the pairing of A with G or T with C. Such mismatches are detected and repaired by the Mutator protein family. These proteins were first described in the bacteria Escherichia coli (E. coli), but homologs appear throughout prokaryotes and eukaryotes.
Mutator S (MutS) initiates the mismatch repair (MMR) by identifying and binding to the mismatch. Subsequently, MutL identifies which strand is the new copy. Only the new strand requires fixing, while the template strand needs to remain intact. How can the molecular machinery identify the newly synthesized strand of DNA?
Newly Synthesized Strands of DNA Differ from Their Template Strand
In many organisms, cytosine and adenine bases of the new strand receive a methyl group sometime after replication. Therefore, Mut proteins identify new strands by recognizing sequences&#160; that have not yet been methylated. Additionally, the newly synthesized strand in eukaryotes is more likely to have small breaks, also called DNA nicks. The MMR proteins can thus identify the nicked strand and target it for repair.
After identification of the new strand, nuclease enzymes cut the affected region and excise the incorrect nucleotides. Next, DNA polymerase fills in the correct nucleotides, and DNA ligase seals the sugar-phosphate backbone of the DNA, thereby completing the mismatch repair process.
Defects in the Mismatch Repair Mechanism Can Cause Cancer
The human homolog of MutS is called Mutator S homolog 2 (MSH2). If MSH2 function is compromised, point mutations and frameshift mutations throughout the genome are not properly repaired. Consequently, humans carrying a single copy of such a compromised MSH2 have a higher likelihood of developing cancer.
Unrepaired Mutations Fuel Adaptation
Would it be best if MMR never missed a mismatch? Even low mutation rates can cause a problem for an organism. However, mutations also contribute to genetic variation in a population. For instance, a permissive mismatch repair system in a bacterium can lead to the mutation of a gene that confers antibiotic resistance, thereby increasing the chances of bacterial survival and reproduction when exposed to antibiotics. This is great news for the bacterial population but bad news for humans that rely on antibiotics to combat infectious diseases.

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the ...

Education

JoVE Core

Cell Biology

Unit 1

DNA Replication and Repair

KEY TERMS AND CONCEPTS

dna mismatch repair and cancer risk

DNA mismatch repair fixes copying errors that happen during DNA replication. It helps cells find the wrong nucleotide, remove it, and replace it with the correct one before the cell divides.

Human cells carry more than 3 billion base pairs of DNA, so replication must be very accurate. Even with DNA polymerase proofreading, a copying error can still occur about once every 1 million base pairs. One common error is a mismatch, such as A paired with G or T paired with C. The Mutator protein family detects and repairs these mistakes. These proteins were first described in Escherichia coli, or E. coli, and similar proteins are found in both prokaryotes and eukaryotes.

MutS starts mismatch repair by binding to the mismatched bases. MutL then helps identify which strand is the new copy. Only the new strand needs to be corrected, while the original template strand must stay intact. In many organisms, the new DNA strand is marked by methyl groups added to cytosine and adenine after replication. In eukaryotes, the new strand is also more likely to contain small breaks called DNA nicks. MMR proteins can use these differences to target the strand that needs repair.

After the new strand is identified, nuclease enzymes cut out the damaged region. DNA polymerase then fills in the missing section with the correct nucleotides. DNA ligase seals the sugar-phosphate backbone and finishes the repair process.

Mismatch repair also matters for human health. The human MutS homolog is called MSH2. If MSH2 is damaged, point mutations and frameshift mutations may not be repaired across the genome. People who carry one compromised copy of MSH2 have a higher chance of developing cancer. At the same time, some unrepaired mutations can help bacteria adapt. A permissive mismatch repair system can allow a mutation that gives antibiotic resistance, which helps bacteria survive and reproduce when antibiotics are present.

DNA Mismatch Repair and Cancer Risk

base-pairing and dna repair

DNA Pairing Rules in Repair

DNA pairing rules help guide DNA repair. In DNA, bases pair in a specific way, and those matching pairs support accurate copying and fixing of the molecule. When DNA is damaged or copied incorrectly, repair systems can use the normal base-pairing pattern as a reference. This helps cells find mismatched bases and restore the correct sequence. The process depends on the idea that each base has a preferred partner. Understanding base-pairing is important because it explains how cells protect...

the dna replication fork

DNA Replication Fork in Action

The DNA replication fork is the active region where DNA copies itself. It forms when the two strands of the double helix separate so each strand can serve as a template for a new partner strand. At the fork, the copying process moves in a set direction. The two strands are built in different ways as replication continues, so the fork helps organize how the new DNA is made. The replication fork is a key part of accurate DNA duplication. It shows how the cell opens the double helix, copies the...

lagging strand synthesis

Okazaki Fragments on the Lagging Strand

Lagging strand synthesis builds new DNA in short pieces called Okazaki fragments. This happens during DNA replication because the lagging strand runs in the opposite direction from the direction the replication machinery moves. As the DNA double helix opens, DNA polymerase adds nucleotides only in the 5' to 3' direction. On the lagging strand, this forces the cell to copy the template in segments instead of one continuous stretch. Each segment begins near the replication fork and extends away...

the replisome

Replisome Components in DNA Copying

The replisome is the protein machine that copies DNA during cell division. It works at the replication fork, where the double helix opens so new strands can be made. DNA polymerase is the core enzyme in the replisome. It adds nucleotides to the growing DNA strand. In bacteria, two DNA polymerases work together at the fork. These enzymes are linked to the helicase by a clamp-like protein so they stay attached to the DNA. Helicase unwinds the DNA ahead of the fork. Single-stranded binding...

proofreading

DNA Polymerase Error Correction

DNA polymerase uses proofreading to help correct errors during DNA replication. As it builds the daughter strand, the enzyme adds nucleotides that match the template DNA strand. This matching helps keep DNA copying accurate and supports replication fidelity. DNA is made in the 5' to 3' direction, and several DNA polymerases help with this process. In nuclear DNA replication, DNA polymerase delta and DNA polymerase epsilon have proofreading ability. After a new base is added, these polymerases...

replication in prokaryotes

How Prokaryotic DNA Copies Itself

Prokaryotic DNA copies itself through a set of coordinated steps called initiation, elongation, and termination. In bacteria, replication starts when initiator proteins bind to a single origin of replication, or ori, on the circular chromosome. The DNA is then copied in both directions until two DNA molecules are made. Several proteins help open and stabilize the DNA during replication. Topoisomerase cuts one side of the double-stranded phosphate-sugar backbone so the helix can unwind faster.

replication in eukaryotes

Eukaryotic DNA Replication Steps

Eukaryotic DNA replication copies the genome before cell division. It happens in a tightly regulated way so each daughter cell gets a complete set of chromosomes in the nucleus. The process has three stages: initiation, elongation, and termination. Eukaryotic cells use many proteins to manage replication because their chromosomes are linear and their genomes are larger than those of prokaryotes. Replication begins at multiple origins of replication along each chromosome. Initiator proteins...

telomeres and telomerase

Telomeres and Telomerase in DNA Replication

Telomeres and telomerase help protect chromosomes during DNA replication. Telomeres are repeated DNA sequences at chromosome ends, and telomerase is the enzyme that can extend them. Together, they help keep important genetic information from being lost when cells divide. Each time a chromosome is copied, the very end of the DNA strand can be difficult to replicate fully. Telomeres act like a buffer zone at the tips of chromosomes. Telomerase adds new repeats to these ends, which helps maintain...

overview of dna repair

DNA Repair and Genetic Recombination

DNA repair and genetic recombination help cells respond to damage in DNA. DNA can be harmed by normal cell activity or by outside factors. When damage is not fixed, it can affect how genetic information is copied and used. Cells use repair pathways to detect and correct many kinds of DNA damage. Some repair steps remove damaged bases or replace missing pieces of DNA. Other pathways help keep the DNA sequence stable after damage has occurred. Genetic recombination is also part of this process.

base excision repair

Base Excision Repair Pathway

Base excision repair is a DNA repair pathway that fixes small base damage. It helps cells correct changes that can appear in DNA before they cause larger problems. In this pathway, a damaged base is removed first. The cell then processes the site and replaces the missing part with the correct DNA building block. This repair step helps keep genetic information accurate. Base excision repair is one of the main ways cells handle everyday DNA damage. It is an important part of maintaining DNA...

nucleotide excision repair

UV Damage and DNA Repair by NER

UV damage can bend DNA and block replication or transcription. Cells often face mutagens, which are outside factors that damage DNA and can create mutations. If these changes are not repaired, they can lead to disease or cancer, depending on which DNA sequences are affected. Nucleotide excision repair, or NER, is the pathway that helps cells find and remove damaged DNA. In prokaryotes, three proteins carry out this work: UvrA, UvrB, and UvrC. UvrA and UvrB move along the DNA together and look...

DNA mismatch repair fixes copying errors that happen during DNA replication. It helps cells find the wrong nucleotide, remove it, and replace it with the correct one before the cell divides. Human cells carry more than 3 billion base pairs of DNA, so replication must be very accurate. Even with DNA polymerase proofreading, a copying error can still occur about once every 1 million base pairs. One common error is a mismatch, such as A paired with G or T paired with C. The Mutator protein family...

dna damage can stall the cell cycle

DNA Repair Checkpoints in the Cell Cycle

DNA repair checkpoints help cells pause the cell cycle after DNA damage. This pause gives the cell time to check for breaks and repair them before division continues. Cells must do this at critical stages of the cycle. The amount of DNA in the cell depends on when the pause happens. If the cycle stops before DNA replication, the cells will contain twice the normal amount of DNA. If cells stop after DNA replication but before mitosis, they will contain four times the normal amount. Cells use...

fixing double-strand breaks

Repairing DNA Double-Strand Breaks

Repairing DNA double-strand breaks is an important part of DNA maintenance. A double-strand break happens when both strands of the DNA molecule are cut. Cells must fix this damage to keep genetic information stable. The repair process can happen by more than one pathway. Some breaks are repaired by direct joining of the broken ends. Other breaks are repaired by using a matching DNA sequence as a template. These pathways help cells respond to damage in different ways. This topic is closely...

homologous recombination

Homologous Recombination in DNA Repair

Homologous recombination is a DNA repair process that uses a matching DNA sequence as a template. It helps cells fix breaks in DNA and keep genetic information accurate. The process begins when a broken DNA strand finds a similar, or homologous, piece of DNA. That matching sequence guides repair and allows the damaged DNA to be restored. Because the repair uses a copied sequence, the final DNA can closely match the original information. Homologous recombination is also important in genetic...

gene conversion

Gene Conversion During DNA Repair

Gene conversion is a DNA repair event linked to genetic recombination. It can change the sequence of one DNA region by using a related DNA strand as a template. This process is important for understanding how cells repair damage and reshuffle genetic information. During recombination, gene conversion can copy information from one DNA molecule to another. The result is not a simple swap of DNA segments. Instead, one sequence is corrected or replaced while the related partner sequence remains...

restarting stalled replication forks

Restarting DNA Replication After Stalls

DNA replication can stop before it is finished when the fork stalls. A stalled replication fork is a point where the DNA-copying machinery slows down or pauses during chromosome duplication. Cells can restart these forks to keep copying DNA. This process helps the replication machinery move forward again after the pause. It is an important part of maintaining normal DNA replication when problems arise during copying. The term stalled replication fork describes the stopped or delayed state of...

key terms and concepts

Learn how mismatch repair fixes DNA copying errors, how cells find the new strand, and why MSH2 defects can raise cancer risk.

DNA Mismatch Repair and Cancer Risk | JoVE K12

cell biology

JoVE Core Cell Biology illustrates complex cellular processes in easy-to-understand yet comprehensive animated video lessons. This collection focuses on the essential components and functions of cells, including organelles and membranes, cellular transport, and cell energetics. It is complemented by scientist-in-action videos that demonstrate the application of cell biology in real-world research experiments.

Texas Essential Knowledge and Skills

High School

BIO.7

BIO.7.C

What is Meiosis?

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Meiosis I

Meiosis II

Meiosis vs. Mitosis

Crossing Over

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Nondisjunction

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Spermatogenesis

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Oogenesis

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Fertilization

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Cleavage and Blastulation

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Gastrulation

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Neurulation

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Use models to explain how DNA is passed from parents to offspring through the processes of meiosis and fertilization in sexual reproduction.

LS.Bio.6.1

Mutations

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genome-size-and-the-evolution-of-new-genes

Genome Size and the Evolution of New Genes

types-of-genetic-transfer-between-organisms

Types of Genetic Transfer Between Organisms

Base-pairing and DNA Repair

The DNA Replication Fork

Lagging Strand Synthesis

The Replisome

Proofreading

Synthesis of new DNA molecules is carried out by the enzyme DNA polymerase, which adds nucleotides on the daughter strand complementary to the template ...

Replication in Prokaryotes

DNA replication has three main steps: initiation, elongation, and termination. Replication in prokaryotes begins when initiator proteins bind to the ...

Replication in Eukaryotes

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Overview of DNA Repair

Base Excision Repair

Nucleotide Excision Repair

DNA Distortion and Damage
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Fixing Double-strand Breaks

Homologous Recombination

Gene Conversion

Restarting Stalled Replication Forks

Construct an explanation to summarize how inheritable genetic variations may result from: new genetic combinations in meiosis, mutations during replication, or mutations caused by environmental factors.

An Overview of Genetic Analysis

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Genetic Crosses

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Punnett Squares

Monohybrid Crosses

Dihybrid Crosses

Trihybrid Crosses

Trihybrid Crosses
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Law of Independent Assortment

Chi-square Analysis

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Pedigree Analysis

Multiple Allele Traits

Incomplete Dominance

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Lethal Alleles

Agouti: A Lethal Allele
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Polygenic Traits

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Background and Environment Affect Phenotype

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Use mathematics and computational thinking to predict the variation and distribution of expressed traits based on: Mendelian inheritance, co-dominance, incomplete dominance, multiple alleles, and sex-linked inheritance.

LS.Bio.7.1

Overview

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Probability Laws

Overview

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The Concept of Multiple Allelism

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Analyze and interpret data to explain how polygenic traits result in a wide range of phenotypes.

LS.Bio.7.2

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause ...

Nature and Nurture

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Construct an explanation to summarize how traits result from interactions of genetic factors (multiple genes and/or alleles) and environmental factors.

LS.Bio.7.3

PCR: The Polymerase Chain Reaction

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DNA Gel Electrophoresis

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DNA Isolation

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Restriction Enzymes

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DNA Agarose Gel Electrophoresis

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dna-isolation-and-restriction-enzyme-analysis

DNA Isolation and Restriction Enzyme Analysis

The revelation of DNA as the hereditary molecule in all organisms has led to enormous scientific and medical breakthroughs and significantly enhanced our ...

Preparation of Solutions and Materials
ExpandNOTE: For this lab to run smoothly, it is recommended to not exceed 12 samples per laboratory class.
First ...

DNA Isolation
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Analyze and interpret data to compare DNA samples.

LS.Bio.8.1

Transgenic Organisms

Reproductive Cloning

CRISPR

Synthetic Biology

Synthetic biology is an interdisciplinary science that involves using principles from disciplines such as engineering, molecular biology, cell biology, ...

Ribosome Profiling

Ribosome profiling or ribo-sequencing is a deep sequencing technique that produces a snapshot of active translation in a cell. It selectively sequences ...

Transgenic Plants

Recombinant DNA technology called transgenesis is often used to add a foreign gene or remove a detrimental gene from an organism. Such genetically ...

Gene Therapy

biofuels-producing-ethanol-from-cellulosic-material

Biofuels: Producing Ethanol from Cellulosic Material

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Testing For Genetically Modified Foods

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Genetic modification of foods has been a controversial issue due to debated ...

Obtain and communicate information that summarizes the impact of biotechnology applications on the individual, society, and the environment, including agriculture and medicine.

LS.Bio.8.2

Understand genetic mechanisms for variation.

DNA Mismatch Repair and Cancer Risk

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