Introduction
Mutation refers to a permanent change in the DNA sequence of a gene. Although DNA is highly stable, occasional errors can occur during replication or due to exposure to environmental factors. Such changes can affect replication, transcription, and translation, leading to altered gene expression or disease.
Substances or agents that induce mutations are called mutagens. These may include radiation, chemicals, or biological agents that modify DNA structure.
Types of Mutations
Mutations are broadly classified into two major types:
- Point Mutations
- Frame-shift Mutations
1. Point Mutations
These occur when one base pair in DNA is replaced by another. Point mutations are further classified into:
- Transitions: Replacement of one purine by another (A ↔ G) or one pyrimidine by another (C ↔ T).
- Transversions: Replacement of a purine by a pyrimidine or vice versa (A ↔ C, G ↔ T, etc.).
2. Frame-shift Mutations
These result from the insertion or deletion of one or more nucleotide bases, altering the reading frame of the genetic code. Consequently, every codon downstream of the mutation is misread, producing a completely altered or truncated protein.
Consequences of Point Mutations
Depending on how the altered codon is read, point mutations can have different outcomes (Fig. 24.15):
1. Silent Mutation
When the change in base sequence does not alter the amino acid sequence of the protein due to the degeneracy of the genetic code. For example, both UCA and UCU code for serine, producing no detectable effect.
2. Missense Mutation
When a base substitution results in a different amino acid. This can affect the protein’s structure and function. The classic example is sickle-cell anemia, caused by substitution of valine for glutamic acid in hemoglobin.
3. Nonsense Mutation
If a base substitution creates a premature stop codon (e.g., UCA → UAA), protein synthesis terminates early, resulting in a shortened, nonfunctional protein.
Consequences of Frame-shift Mutations
Insertion or deletion of bases alters the reading frame of mRNA, producing abnormal codons and often a nonfunctional or truncated protein. Since there are no punctuation marks in genetic coding, translation proceeds incorrectly until a stop codon appears.
Mutations and Cancer
Mutations play a major role in the development of cancer. They cause permanent alterations in DNA structure that can activate oncogenes or deactivate tumor suppressor genes, leading to uncontrolled cell proliferation. Mutagens such as UV radiation and chemical carcinogens are strongly linked to cancer formation.
DNA Repair Mechanisms
Cells possess highly specialized mechanisms to correct DNA damage caused by replication errors or environmental mutagens. These repair systems maintain genetic stability and prevent diseases. Four main repair mechanisms are recognized:
- Base Excision Repair (BER)
- Nucleotide Excision Repair (NER)
- Mismatch Repair (MMR)
- Double-Strand Break Repair (DSBR)
1. Base Excision Repair (BER)
This mechanism removes abnormal bases formed by spontaneous deamination or oxidation. Common examples include conversion of cytosine to uracil, adenine to hypoxanthine, and guanine to xanthine.
Steps:
- Recognition: The enzyme uracil DNA glycosylase identifies and removes the defective base.
- Excision: An endonuclease cuts the DNA backbone near the damaged site and removes a few bases.
- Replacement: The gap is filled by DNA polymerase.
- Sealing: DNA ligase seals the nick to restore DNA integrity.
2. Nucleotide Excision Repair (NER)
NER corrects large-scale DNA damage such as thymine dimers caused by UV radiation or bulky chemical adducts.
Steps:
- Recognition of the damaged region.
- Unwinding of DNA around the lesion.
- Excision by excision nuclease (exinuclease) on both sides of the damage.
- Replacement of the missing nucleotides by DNA polymerase.
- Rejoining of the repaired strand by DNA ligase.
Clinical Correlation:
Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder resulting from a defect in NER. Patients are extremely sensitive to sunlight and prone to skin cancers due to an inability to repair UV-induced DNA damage.
3. Mismatch Repair (MMR)
During DNA replication, occasional mispairing occurs (e.g., C opposite A instead of T). The MMR system corrects such errors immediately after replication.
Mechanism:
- The template (original) DNA strand is methylated; the new strand is not.
- GATC endonuclease recognizes the mismatch and cuts the unmethylated (new) strand at the GATC sequence.
- An exonuclease removes the defective segment.
- DNA polymerase synthesizes the correct sequence, and DNA ligase seals the strand.
Clinical Correlation:
Hereditary Nonpolyposis Colon Cancer (HNPCC) is associated with a defect in mismatch repair genes, leading to accumulation of replication errors and cancer formation.
4. Double-Strand Break Repair (DSBR)
Double-strand breaks (DSBs) are among the most dangerous DNA damages as they can lead to chromosomal fragmentation, translocations, or cell death.
Repair Mechanisms:
- Homologous Recombination (HR): Uses a homologous sequence as a template to repair the break accurately (common in yeast and dividing cells).
- Non-Homologous End Joining (NHEJ): Directly rejoins broken DNA ends without a template. It is the dominant repair mechanism in mammalian cells.
Summary Table: Types of Mutation and DNA Repair Mechanisms
| Type | Cause/Mechanism | Consequence | Example/Clinical Link |
|---|---|---|---|
| Point Mutation | Base substitution (transition or transversion) | Change in one amino acid or stop codon | Sickle-cell anemia |
| Frame-shift Mutation | Insertion or deletion of base pairs | Altered reading frame, truncated protein | β-thalassemia |
| Base Excision Repair | Removes damaged bases | Restores normal DNA sequence | Uracil DNA glycosylase system |
| Nucleotide Excision Repair | Removes bulky DNA lesions | Replaces damaged segment | Xeroderma Pigmentosum |
| Mismatch Repair | Corrects replication errors | Maintains DNA fidelity | HNPCC (Colon cancer) |
| Double-Strand Break Repair | Repairs broken DNA strands | Prevents chromosomal damage | HR and NHEJ pathways |
Detailed Notes:
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