13.3 DNA damage and repair mechanisms
3 min read•july 22, 2024
DNA damage is a constant threat to our genetic material. From environmental factors to cellular processes, our DNA faces various forms of assault. Luckily, our cells have evolved sophisticated repair mechanisms to combat this damage and maintain genomic integrity.
These repair systems work tirelessly to fix different types of DNA damage. From small base modifications to major strand breaks, each mechanism targets specific issues. When repair fails, the consequences can be severe, leading to mutations, , and even diseases like cancer.
Types of DNA Damage and Repair Mechanisms
Types of DNA damage
Top images from around the web for Types of DNA damage
Frontiers | Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review View original
Is this image relevant?
DNA Damage: Proteins pinpoint double strand breaks | eLife View original
Is this image relevant?
Frontiers | Mechanism and Control of Meiotic DNA Double-Strand Break Formation in S. cerevisiae View original
Is this image relevant?
Frontiers | Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review View original
Is this image relevant?
DNA Damage: Proteins pinpoint double strand breaks | eLife View original
Is this image relevant?
1 of 3
Top images from around the web for Types of DNA damage
Frontiers | Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review View original
Is this image relevant?
DNA Damage: Proteins pinpoint double strand breaks | eLife View original
Is this image relevant?
Frontiers | Mechanism and Control of Meiotic DNA Double-Strand Break Formation in S. cerevisiae View original
Is this image relevant?
Frontiers | Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review View original
Is this image relevant?
DNA Damage: Proteins pinpoint double strand breaks | eLife View original
Is this image relevant?
1 of 3
- Base modifications occur when DNA bases are chemically altered (oxidation, deamination, alkylation)
- happen when one strand of the DNA double helix is severed (reactive oxygen species, ionizing radiation)
- involve both strands of the DNA double helix being broken (ionizing radiation, replication fork collapse, certain chemotherapeutic agents like cisplatin)
DNA repair mechanisms
- (BER) fixes small base modifications
- Glycosylase enzymes recognize and remove damaged bases creating an apurinic/apyrimidinic (AP) site
- AP endonuclease nicks the DNA backbone at the AP site
- fills in the missing nucleotide
- seals the remaining nick completing the repair
- (NER) handles bulky lesions and helix-distorting damage
- Damage is recognized through global genome NER or transcription-coupled NER
- Damaged strand is excised creating a gap
- DNA polymerase synthesizes new DNA to fill the gap
- DNA ligase seals the nick restoring the intact DNA strand
- (MMR) corrects mismatched bases and small insertion/deletion loops
- identifies base mismatches and insertion/deletion loops
- recruits to nick the newly synthesized strand
- Mismatched strand is excised by
- DNA polymerase fills in the gap with the correct nucleotides
- DNA ligase seals the remaining nick completing MMR
DNA Damage Response and Consequences
DNA damage checkpoints
- prevents cells with damaged DNA from entering S phase
- tumor suppressor protein is activated and induces expression
- p21 inhibits cyclin-dependent kinases halting the cell cycle
- slows down DNA replication when damage is detected during S phase
- senses single-stranded DNA and activates
- Chk1 phosphorylates and inhibits proteins involved in DNA replication
- stops cells with damaged DNA from entering mitosis
- ATM kinase is activated by double-strand breaks and phosphorylates
- Chk2 phosphorylates and inhibits Cdc25 phosphatase preventing mitotic entry
- DNA damage checkpoints maintain genomic integrity by
- Allowing time for repair before cell cycle progression
- Preventing the transmission of mutations to daughter cells
- Triggering if the damage is irreparable
Consequences of unrepaired damage
- Mutations arise from unrepaired DNA damage
- Point mutations include base substitutions, insertions, or deletions
- involve larger scale changes (translocations, deletions, duplications)
- Genomic instability refers to an increased tendency for mutations and chromosomal changes
- occurs when mismatch repair is defective
- Chromosomal instability involves frequent changes in chromosome structure and number
- Consequences of unrepaired DNA damage and genomic instability include
- Increased risk of developing cancer due to accumulation of mutations in oncogenes and tumor suppressors
- Accelerated aging as seen in progeroid syndromes caused by defects in DNA repair pathways
- Inherited genetic disorders when mutations are passed down through the germline (Fanconi anemia, Bloom syndrome)
Key Terms to Review (28)
Apoptosis: Apoptosis is a programmed cell death process that plays a crucial role in maintaining cellular homeostasis and regulating development. This highly controlled mechanism allows the body to eliminate damaged, unwanted, or potentially harmful cells without triggering inflammation, connecting tightly with various cellular processes and signaling pathways.
Atr kinase: ATR kinase, or Ataxia Telangiectasia and Rad3-related kinase, is a crucial protein involved in the cellular response to DNA damage and stress signals. It plays a key role in the activation of cell cycle checkpoints, particularly in response to DNA damage, ensuring that cells do not progress through the cell cycle until the damage is repaired. By phosphorylating various substrates, ATR kinase coordinates repair mechanisms, signaling pathways, and cell cycle regulation.
Base excision repair: Base excision repair is a cellular mechanism that corrects DNA damage caused by the removal of damaged or non-canonical bases. This process is essential for maintaining genomic stability by fixing small, non-helix-distorting base lesions that may result from environmental factors or normal cellular metabolism. By efficiently identifying and excising damaged bases, base excision repair prevents mutations that could lead to diseases, including cancer.
Carcinogenesis: Carcinogenesis is the process by which normal cells transform into cancerous cells through a series of genetic and cellular changes. This process involves multiple stages, including initiation, promotion, and progression, often triggered by various environmental factors or mutations in DNA. Understanding this process is crucial for developing preventive measures and treatments for cancer.
Chk1 kinase: Chk1 kinase is a serine/threonine protein kinase that plays a crucial role in the DNA damage response and cell cycle regulation. It helps maintain genomic stability by mediating cell cycle arrest in response to DNA damage, allowing for repair mechanisms to function properly. When DNA damage occurs, Chk1 kinase is activated, which leads to the inhibition of cell cycle progression and facilitates the repair process.
Chk2 kinase: Chk2 kinase is a serine/threonine protein kinase that plays a crucial role in the DNA damage response and cell cycle regulation. It acts as a checkpoint protein, helping to coordinate the cellular response to DNA damage by activating repair mechanisms and, if necessary, triggering apoptosis to eliminate damaged cells.
Chromosomal aberrations: Chromosomal aberrations are structural or numerical alterations in chromosomes that can lead to various genetic disorders and diseases, including cancer. These abnormalities can occur through mechanisms such as breaks, deletions, duplications, inversions, or aneuploidy, which can impact gene expression and cellular function. Understanding chromosomal aberrations is crucial because they are often linked to DNA damage and repair mechanisms, as well as the hallmarks of cancer and oncogenic transformation.
Dna damage response pathway: The DNA damage response pathway is a complex network of cellular processes that detect and repair damaged DNA to maintain genomic integrity. This pathway activates a series of signaling cascades that respond to various types of DNA damage, such as breaks, mismatches, and chemical modifications. By coordinating repair mechanisms and regulating cell cycle progression, the pathway plays a critical role in preventing mutations and protecting against cancer development.
Dna ligase: DNA ligase is an essential enzyme that facilitates the joining of DNA strands by forming phosphodiester bonds between the 3' hydroxyl and 5' phosphate ends of adjacent nucleotides. This process is critical for sealing nicks in the DNA backbone during DNA replication, repair, and recombination, ensuring the integrity of the genetic material across various cellular processes.
DNA polymerase: DNA polymerase is an enzyme that synthesizes new strands of DNA by adding nucleotides to a pre-existing DNA template strand during the processes of DNA replication and repair. This enzyme plays a crucial role in ensuring the accuracy and efficiency of genetic information transmission, connecting it to how nucleic acids function structurally and functionally, as well as their involvement in various cellular processes such as DNA repair mechanisms and molecular biology techniques used in research.
Double-strand breaks: Double-strand breaks (DSBs) are severe forms of DNA damage where both strands of the DNA helix are broken, leading to the disruption of genetic information. DSBs can arise from various sources such as ionizing radiation, chemical agents, and normal cellular processes. If not repaired correctly, they can lead to mutations, cell death, or diseases like cancer.
Exonuclease enzymes: Exonuclease enzymes are specialized proteins that play a crucial role in nucleic acid metabolism by removing nucleotides from the ends of DNA or RNA molecules. They are essential for various cellular processes, including DNA replication, repair, and degradation, ensuring the integrity of genetic material. Their activity is vital in maintaining genomic stability and correcting errors that may arise during DNA synthesis or following DNA damage.
G1/S Checkpoint: The G1/S checkpoint is a critical control mechanism in the cell cycle that assesses whether a cell is ready to enter the synthesis (S) phase and replicate its DNA. This checkpoint evaluates the integrity of the DNA, the size of the cell, and the availability of necessary nutrients and growth factors, ensuring that only healthy and appropriately sized cells proceed to DNA synthesis.
G2/M Checkpoint: The G2/M checkpoint is a crucial regulatory point in the cell cycle that occurs before a cell enters mitosis. It ensures that all DNA has been accurately replicated and that there are no DNA damages or errors before the cell divides. This checkpoint plays a significant role in maintaining genomic stability and preventing the propagation of damaged DNA to daughter cells.
Gel electrophoresis: Gel electrophoresis is a laboratory technique used to separate and analyze macromolecules like DNA, RNA, and proteins based on their size and charge. By applying an electric field to a gel matrix, charged molecules move through the gel, allowing researchers to visualize distinct bands corresponding to different fragments. This method is essential in various applications, including DNA structure analysis, studying DNA damage and repair, and examining gene expression regulation.
Genomic instability: Genomic instability refers to an increased tendency of the genome to acquire mutations and abnormalities over time, leading to changes in the structure or number of chromosomes. This phenomenon is often a result of defects in DNA damage response mechanisms, which can result in cancer and other diseases due to uncontrolled cell division and the accumulation of genetic alterations.
Intra-S checkpoint: The intra-S checkpoint is a critical regulatory mechanism in the cell cycle that ensures the integrity of DNA during the synthesis (S) phase. This checkpoint monitors the replication of DNA, detecting any DNA damage or replication stress, and prevents the cell from progressing to the next phase until these issues are resolved. By doing so, it plays a crucial role in maintaining genomic stability and preventing the propagation of damaged DNA.
Microsatellite instability: Microsatellite instability (MSI) refers to the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR) mechanisms, leading to alterations in the length of microsatellite regions. This phenomenon is often associated with various types of cancer, particularly colorectal cancer, and signifies a failure in the cell's ability to correct errors that occur during DNA replication. The presence of MSI can serve as a biomarker for identifying tumors with defective MMR pathways.
Mismatch repair: Mismatch repair is a critical cellular process that corrects errors that occur during DNA replication, specifically when the wrong nucleotide is incorporated into the newly synthesized strand. This mechanism is essential for maintaining genetic stability, as it prevents mutations that could lead to various diseases, including cancer. By recognizing and repairing these mismatched bases, the cell ensures the fidelity of genetic information passed on during cell division.
Muth endonuclease: Muth endonuclease is a critical enzyme involved in DNA repair mechanisms, particularly in the recognition and excision of damaged DNA segments. This enzyme plays a vital role in maintaining genomic integrity by removing mismatched bases and preventing mutations that could lead to disease. The proper functioning of muth endonuclease is essential for cellular health, as it ensures that DNA remains stable and accurately replicated.
Mutl protein: mutl protein is a crucial component of the DNA mismatch repair system, responsible for recognizing and repairing mismatches that occur during DNA replication. This protein plays a key role in maintaining genomic stability by ensuring the accuracy of DNA replication, which helps prevent mutations that could lead to diseases like cancer. The proper function of mutl protein is vital for cellular health and longevity.
Muts protein: The muts protein is a key component of the DNA mismatch repair (MMR) system, which helps maintain genomic stability by recognizing and repairing errors that occur during DNA replication. By detecting mispaired bases and initiating repair processes, muts plays a crucial role in preventing mutations that could lead to diseases like cancer. Its function highlights the importance of cellular mechanisms that safeguard DNA integrity.
Nucleotide excision repair: Nucleotide excision repair is a DNA repair mechanism that removes bulky DNA lesions, such as those caused by ultraviolet (UV) light and certain chemical agents. This process involves the recognition of damaged DNA, excision of the damaged section, and subsequent resynthesis of the missing DNA using the complementary strand as a template. It is crucial for maintaining genomic integrity and preventing mutations that could lead to diseases like cancer.
P21: p21 is a cyclin-dependent kinase inhibitor (CDKI) that plays a crucial role in regulating the cell cycle and maintaining genomic stability. It is primarily activated in response to DNA damage, acting as a key mediator of cell cycle arrest by inhibiting cyclin-dependent kinases, thus preventing cells from progressing through the cell cycle until damage is repaired.
P53: p53 is a critical tumor suppressor protein that plays a pivotal role in regulating the cell cycle, maintaining genomic stability, and preventing tumor formation. Often referred to as the 'guardian of the genome,' p53 responds to cellular stress signals, including DNA damage, by initiating DNA repair processes, inducing apoptosis in severely damaged cells, and influencing various cellular pathways related to growth and survival.
Point Mutation: A point mutation is a change in a single nucleotide base pair in the DNA sequence, which can lead to alterations in gene function. This type of mutation can have varying effects on protein synthesis, ranging from no effect at all to causing significant changes in the resulting protein. Understanding point mutations is crucial as they play a key role in genetic diversity, disease development, and the overall functionality of nucleic acids.
Single-strand breaks: Single-strand breaks are disruptions in the DNA structure where only one of the two strands is severed, leading to a temporary loss of integrity in the DNA helix. These breaks can occur due to various factors, including oxidative stress, radiation, and certain chemical agents. While they are less severe than double-strand breaks, if left unrepaired, single-strand breaks can compromise genomic stability and lead to mutations or cell death.
Transcriptional activation: Transcriptional activation is the process by which specific proteins, known as transcription factors, increase the likelihood of transcription of particular genes. This involves the binding of these factors to enhancer or promoter regions of DNA, which can lead to a greater synthesis of RNA from those genes. This process is crucial for regulating gene expression in response to various signals and cellular conditions.