Name: dna repair checkpoints in the cell cycle
Uploaded: 2025-12-12T13:26:51.000Z
Duration: 2 min 36 s
Channel: JoVE

K12 Standards

Louisiana Student Standards for Science

High School

Life Sciences

heredity-inheritance-and-variation-of-traits

Heredity: Inheritance And Variation Of Traits

HS-LS3-3

DNA Damage Can Stall the Cell Cycle

At various checkpoints during the cell cycle, multiple enzymes probe the DNA for damage. To maintain the integrity of the genome, only intact, undamaged DNA is allowed to pass through this cycle, and on to the next generation. If DNA damage is detected, the cell cycle pauses until this is repaired.During DNA replication in the S phase, helicase unwinds the DNA, and DNA polymerase synthesizes a new strand from the template - creating a Y-shaped structure called a replication fork. Damaged DNA stalls the replication fork, causing it to become unstable, and the helicase and polymerase to uncouple from the DNA.To prevent the damaged single-stranded DNA from reannealing, replication protein A or RPA, coats the single-stranded DNA at the stalled replication fork. This complex is then detected by the ATR protein, also known as ataxia telangiectasia or Rad-3 related protein.If the damaged DNA is not a single mutation but a full double strand break, a protein complex called MRN is recruited at the site, which bridges the two damaged ends of the DNA and provides a platform for binding of the ataxia-telangiectasia mutated, or ATM protein.Both ATM and ATR are kinases, which means they catalyze the transfer of phosphate groups from phosphate-donating molecules such as NTPs, to specific substrates.ATR and ATM phosphorylate the downstream kinases Chk1 and Chk2, respectively. Chk1 and Chk2 phosphorylate CDC25, which prevents it from accepting further phosphates from CDK1. CDK1 is the regulator of the cell cycle, and as long as it remains inactive, this prevents the cell from progressing to the S phase.Another target of ATR and ATM phosphorylation is the transcription activator protein p53. Phosphorylated p53 can directly bind to DNA, which stimulates another gene to produce a protein called p21. p21 inhibits the cell division-stimulating protein cdk2, preventing the cell from progressing to the next stage of cell division.

dna damage can stall the cell cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at the right time for damage response in a tightly regulated cell cycle.
Replication stress caused by damaged DNA initiates a carefully choreographed pathway of proteins that respond to the specific type of damage with an appropriate repair mechanism. For example, ionizing radiation that can cause double-stranded breaks in DNA activates ATM protein that sets in motion a chain of molecular interactions that involve repair mechanisms such as Non-homologous End Joining, Homologous Repair, and Nucleotide Excision Repair pathway. Kinases like ATM and ATR respond to replication blocks in two distinct processes that operate on different timescales: (i) relatively fast post-translational modifications like phosphorylation of downstream kinases ultimately leading to the inhibition of the cell cycle phosphatase CDC25 required for CDK activation (ii) slower transcriptional regulations, the most well-studied of which, is the role of p53.
p53 is a transcription factor that can regulate the expression of proteins that play critical roles in cell cycle arrest, apoptosis, or senescence. In healthy cells, p53 is maintained in low concentrations. Upon detecting double-strand breaks, ATM activates p53 by phosphorylation. This results in the expression of the CDK inhibitor p21 and the pro-apoptotic BAX and PUMA proteins. p21 arrests cell cycle by inhibiting cyclin&#8211;CDK complexes that phosphorylate proteins mediating G1 to S phase transition. Hence, p53 is critical to the G1/S checkpoint mechanism. In cells where p53 is mutated or absent, cell division can no longer be regulated, and such an uncontrolled cell division results in malignant tumors. Additionally, p53 can directly activate repair pathways such as NER via the regulation of factors that mediate Nucleotide Excision Repair and induce dNTP synthesis.

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages ...

Education

JoVE Core

Cell Biology

Unit 1

DNA Replication and Repair

KEY TERMS AND CONCEPTS

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 specialized proteins to respond to damage in a tightly controlled way. Replication stress from damaged DNA starts a pathway that matches the repair response to the type of damage. For example, ionizing radiation can cause double-stranded DNA breaks, which activate ATM protein.

ATM starts a chain of molecular interactions that can lead to Non-homologous End Joining, Homologous Repair, and Nucleotide Excision Repair. Kinases such as ATM and ATR respond to replication blocks in two ways. One response is fast and uses post-translational modifications, such as phosphorylation, to inhibit CDC25, a cell cycle phosphatase needed for CDK activation.

The other response is slower and depends on transcriptional regulation. The best-known example is p53, a transcription factor that controls proteins involved in cell cycle arrest, apoptosis, or senescence. In healthy cells, p53 stays at low levels.

When double-strand breaks are detected, ATM phosphorylates p53. This activates expression of the CDK inhibitor p21 and the pro-apoptotic proteins BAX and PUMA. p21 stops the cell cycle by blocking cyclin-CDK complexes that drive the G1 to S phase transition, so p53 is important for the G1/S checkpoint.

If p53 is mutated or missing, cell division can lose proper control. Unchecked division can lead to malignant tumors. p53 can also help trigger repair pathways such as NER by regulating factors involved in Nucleotide Excision Repair and by promoting dNTP synthesis.

DNA Repair Checkpoints in the Cell Cycle

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...

mismatch repair

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...

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 DNA damage activates checkpoint proteins like ATM, ATR, and p53 to pause the cell cycle, trigger repair, or stop damaged cells from dividing.

DNA Repair Checkpoints in the Cell Cycle | 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

Biology

BIO.7

BIO.7.C

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Chromosome Replication

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The Nucleosome

DNA in a human cell is almost 2m long and it is packed inside a tiny nucleus that is only a few microns in diameter. The level of compaction of DNA inside ...

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Spreading of Chromatin Modifications

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Histone variants are the histone proteins with structural and sequence variations. These variants may be regarded as &#8220;mutant&#8221; forms that ...

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Euchromatin

The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions ...

Heterochromatin

chromatin-position-affects-gene-expression

Chromatin Position Affects Gene Expression

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Punnett Squares

Monohybrid Crosses

Dihybrid Crosses

Trihybrid Crosses

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Law of Independent Assortment

Chi-square Analysis

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Background and Environment Affect Phenotype

Although the genetic makeup of an organism plays a major role in determining the phenotype, there are also several environmental factors, such as ...

Formulate, refine, and evaluate questions to clarify relationships about the role of DNA and chromosomes in coding the instructions for characteristic traits passed from parents to offspring. Emphasis should be on traits including completely dominant, codominant, incompletely dominant, and sex-linked traits (e.g., pedigrees, karyotypes, genetic disorders, Punnett squares). Examples do not need to include dihybrid crosses.

HS-LS3-1

X and Y Chromosomes

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Meiosis II

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Make and defend a claim based on evidence that inheritable genetic variations may result from: (1) new genetic combinations through meiosis, (2) viable errors occurring during replication, and/or (3) mutations caused by environmental factors. Emphasis is on using data to support arguments for the way variation occurs. Claims should not include the phases of meiosis or the biochemical mechanisms of specific steps in the process.

HS-LS3-2

Mutations

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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

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Replication in Eukaryotes

In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before ...

Telomeres and Telomerase

Fixing Double-strand Breaks

Homologous Recombination

Gene Conversion

What is Gene Expression?

A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised&#160; of nucleotides and proteins are ...

Apply concepts of statistics and probability to explain the variation and distribution of expressed traits in a population. Emphasis is on distribution and variation of traits in a population and the use of mathematics (e.g., calculations of frequencies in Punnett squares, graphical representations) to describe the distribution.

DNA Repair Checkpoints in the Cell Cycle

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