DNA fidelity refers to the accuracy with which an organism’s genetic information is maintained and copied. This precision is fundamental for preserving the stability of the genetic code, ensuring cells function correctly. It allows traits to be passed accurately from one generation to the next. Accurate DNA duplication is essential for the health and proper development of all living organisms.
Precision in DNA Replication
The cell employs mechanisms to ensure accuracy during DNA replication, the process of copying its genetic material. A primary mechanism involves DNA polymerase enzymes, which synthesize new DNA strands. These enzymes not only add nucleotides but also possess a “proofreading” ability.
As DNA polymerase adds new bases to the growing strand, it simultaneously checks for correct base pairing. If an incorrect nucleotide is incorporated, the enzyme detects the mismatch due to structural distortions. The polymerase then uses its 3′ to 5′ exonuclease activity to remove the erroneous nucleotide immediately before continuing synthesis. This real-time error-checking enhances replication fidelity, reducing errors to approximately one mistake per 10^8 to 10^10 nucleotides polymerized. This immediate correction during synthesis represents the first line of defense against replication errors.
Correcting Errors: DNA Repair Pathways
Despite the high accuracy of DNA polymerase proofreading, some errors inevitably escape detection. DNA is also constantly exposed to damaging agents from both internal cellular processes and external environmental sources. To address this, cells possess an array of DNA repair pathways that act as a second line of defense to maintain genomic integrity. These systems monitor and correct damage or errors that occur after replication or from other sources.
One such system is mismatch repair (MMR), which targets base-pairing errors missed by proofreading during replication. MMR proteins identify mismatched bases and small insertions or deletions, then remove the incorrect segment and resynthesize it accurately. Nucleotide excision repair (NER) is another pathway that addresses larger distortions or bulky lesions in the DNA helix, such as those caused by ultraviolet (UV) light exposure or certain chemical mutagens. NER involves removing a larger section of the damaged strand, followed by synthesis of a new, correct segment.
Base excision repair (BER) focuses on fixing minor damage to individual DNA bases, often resulting from oxidation, deamination, or alkylation. In BER, a specific DNA glycosylase enzyme recognizes and removes the damaged base, creating an empty site. An enzyme called AP endonuclease then cleaves the sugar-phosphate backbone, and the gap is filled by DNA polymerase and sealed by DNA ligase. These diverse repair mechanisms work in concert to ensure the integrity of the genetic code.
Consequences of Lost Fidelity
When DNA fidelity is compromised and errors or damage accumulate beyond the cell’s repair capabilities, implications arise for an organism’s health and survival. Such failures directly lead to mutations, which are permanent alterations in the DNA sequence. These mutations can have wide-ranging effects, from subtle changes to severe disruptions in gene function.
Mutations in germline cells, which are reproductive cells, can be passed down to offspring, leading to inherited genetic disorders. Examples include cystic fibrosis or sickle cell anemia, where a single gene mutation can cause widespread physiological effects. In somatic cells, which are all other body cells, accumulating mutations are a primary driver of cancer development and progression. Uncontrolled cell growth, a hallmark of cancer, often results from mutations in genes that regulate cell division or tumor suppression.
A decline in DNA fidelity and a decrease in the efficiency of DNA repair mechanisms are recognized contributors to the aging process. As DNA damage accumulates over time, it can impair cellular functions, leading to tissue degeneration and age-related diseases. Severe or widespread DNA damage can also trigger cell dysfunction or programmed cell death, known as apoptosis. This cellular suicide mechanism prevents damaged cells from proliferating, but excessive apoptosis can lead to tissue loss and organ failure.