DNA Repair

Introduction to DNA Repair

DNA repair is a collection of processes by which a cell identifies and corrects damage to its DNA molecules. These mechanisms are essential for maintaining genetic stability and preventing mutations that can lead to diseases such as cancer.

• DNA damage occurs spontaneously and due to environmental factors.

• Repair mechanisms are crucial for cell survival and proper function.

• Defects in DNA repair pathways can result in inherited human syndromes.

Inherited Human Syndromes with Defects in DNA Repair

Genetic Disorders Linked to DNA Repair Deficiency

Several human syndromes are caused by mutations in genes responsible for DNA repair. These disorders often present with increased cancer risk, developmental abnormalities, and genome instability.

Example: Brca1 and Brca2 mutations are associated with hereditary breast and ovarian cancer, often passed down in families.

Endogenous DNA Lesions and Repair Rates

Types and Frequency of DNA Lesions

Cells experience various types of DNA lesions daily, which are repaired by specific mechanisms. The table below summarizes common endogenous DNA lesions and their repair rates in a diploid mammalian cell over 24 hours.

Key Point: Depurination is the most frequent spontaneous lesion, with thousands of events per cell per day.

Types of DNA Damage

Chemical and Physical DNA Lesions

DNA can be damaged by hydrolytic attack, oxidation, and methylation. The most common types include:

• Depurination: Loss of purine bases (adenine or guanine) from DNA.

• Deamination: Conversion of cytosine to uracil, or 5-methylcytosine to thymine.

• Oxidative damage: Formation of 8-oxo-guanine and other oxidized bases.

• Thymine dimers: Covalent linkage of adjacent thymine bases due to UV radiation.

• Methylation: Addition of methyl groups to DNA bases, which can be mutagenic if not properly repaired.

Example: UV radiation induces thymine dimers, which distort the DNA helix and block replication.

Mechanisms of DNA Damage and Mutation Consequences

Depurination and Deamination

Depurination and deamination are spontaneous chemical reactions that alter DNA bases, potentially leading to mutations if unrepaired.

• Depurination: Removal of a purine base (guanine or adenine) creates an abasic site, which can result in deletion mutations during replication.

• Deamination: Conversion of cytosine to uracil changes base-pairing properties, leading to transition mutations (e.g., G:C to A:T).

Example: If a cytosine is deaminated to uracil and not repaired, DNA replication will pair uracil with adenine, resulting in a G:C to A:T transition.

Mutation Consequences

Unrepaired DNA lesions can result in permanent mutations after DNA replication.

• Base substitution: Deamination of cytosine to uracil leads to a G:C to A:T transition.

• Base deletion: Depurination can cause the loss of a nucleotide pair.

Example: A depurinated adenine site may result in the deletion of an A-T pair after replication.

Physical DNA Damage: UV-Induced Lesions

Thymine Dimers

Exposure to ultraviolet (UV) radiation causes the formation of thymine dimers, which are covalent bonds between adjacent thymine bases on a DNA strand.

• Thymine dimers distort the DNA helix and block DNA replication and transcription.

• Specialized repair mechanisms, such as nucleotide excision repair, are required to remove these lesions.

Example: Xeroderma pigmentosum patients are unable to repair thymine dimers efficiently, leading to extreme UV sensitivity and increased skin cancer risk.

Cell Cycle Effects of DNA Damage

DNA Damage and Cell Cycle Progression

DNA damage can delay progression through the cell cycle, allowing time for repair before cell division. This is a critical checkpoint to prevent the propagation of mutations.

• Cell cycle checkpoints detect DNA damage and halt progression until repair is complete.

• Failure to repair DNA before division can result in cell death or cancer.

Major Mechanisms of DNA Repair

Overview of DNA Repair Pathways

Cells utilize several distinct mechanisms to repair different types of DNA damage. Each pathway is specialized for particular lesions.

• Direct repair: Reversal of specific DNA damage without removing the base.

• Base excision repair (BER): Removal and replacement of damaged bases.

• Nucleotide excision repair (NER): Removal of bulky lesions, such as thymine dimers.

• Translesion DNA polymerase: Specialized polymerases that replicate past DNA lesions.

• Non-homologous end joining (NHEJ): Direct ligation of double-strand breaks without a template.

• Homologous recombination (HR): Accurate repair of double-strand breaks using a homologous template.

Example: Nucleotide excision repair removes thymine dimers and other bulky adducts from DNA.

Summary Table: DNA Repair Mechanisms

Key Terms and Definitions

• Depurination: Loss of a purine base from DNA.

• Deamination: Removal of an amino group from a base, changing its identity.

• Thymine dimer: Covalent linkage of two adjacent thymine bases due to UV light.

• Homologous recombination: Repair of double-strand breaks using a homologous DNA template.

• Non-homologous end joining: Direct joining of DNA ends without a template.

Relevant Equations

While DNA repair is primarily a biochemical process, some relevant equations include:

• Mutation rate:

• Repair efficiency:

Additional info: The notes have been expanded with academic context and definitions to ensure completeness and clarity for exam preparation.