Genetic stability describes a cell’s capacity to preserve the integrity of its DNA sequence and chromosome structure across generations. This ability is important for the proper functioning and survival of all living organisms. Maintaining this stability prevents changes in the genetic blueprint, ensuring cells perform their designated roles accurately. It is a continuous process that underlies the health and propagation of life.
How Cells Maintain Genetic Stability
Cells employ mechanisms to ensure their genetic material remains accurate during replication. DNA polymerase, the enzyme responsible for copying DNA, exhibits high fidelity by carefully selecting the correct nucleotide to add to the growing strand. This enzyme also has a proofreading function, allowing it to detect and remove incorrectly incorporated nucleotides immediately. This significantly reduces error rates to approximately one mistake per 10 billion nucleotides.
Beyond replication, cells possess various DNA repair mechanisms to correct damage. Base excision repair (BER) targets minor damage to individual DNA bases, such as those caused by oxidation or deamination, by removing the damaged base. Nucleotide excision repair (NER) addresses bulkier lesions, like those induced by UV radiation, by excising a damaged segment and synthesizing a new one using the undamaged strand as a template.
Mismatch repair (MMR) is another system that corrects errors, including mispaired bases and small insertions or deletions, missed during DNA replication proofreading. For more severe damage, such as double-strand breaks, cells utilize two main pathways. Homologous recombination (HR) is a precise repair mechanism that uses a homologous chromosome or sister chromatid as a template to mend the break, active during the S and G2 phases.
Non-homologous end joining (NHEJ) is a more error-prone but quick repair pathway for double-strand breaks, active in the G1 phase. This mechanism directly ligates the broken ends, often resulting in small insertions or deletions. In addition to these repair systems, cell cycle checkpoints act as surveillance, pausing cell division if DNA damage is detected.
These checkpoints, located at various stages like G1/S and G2/M, prevent cells with damaged or incompletely replicated DNA from progressing through division. If the damage is too extensive to repair, these checkpoints can trigger programmed cell death, preventing propagation of compromised cells.
The Impact of Losing Genetic Stability
When the systems maintaining genetic stability fail, consequences can arise, leading to alterations in the genetic code. These alterations manifest as mutations, changes in the DNA sequence, or chromosomal aberrations, larger-scale changes in chromosome structure or number. Examples of chromosomal aberrations include aneuploidy, where cells have an abnormal number of chromosomes, or structural rearrangements like translocations, deletions, and amplifications.
The accumulation of these genetic changes can disrupt normal cellular functions. Such instability is linked to the development of various diseases, with cancer being a key example. Genetic instability can expedite cancer development by increasing mutations in genes regulating cell growth and survival.
This heightened rate of mutation can lead to uncontrolled cell proliferation, a characteristic of cancer. Chromosomal instability, a type of genetic instability, can result in the formation of micronuclei, small nuclei separate from the main nucleus. These micronuclei can contribute to genomic rearrangements and epigenetic dysregulation, accelerating cancer progression and potentially leading to drug resistance.
Genetic instability also plays a role in the aging process. As organisms age, there is an accumulation of somatic mutations and DNA damage in normal cells. This age-related decline in the efficiency of DNA repair mechanisms contributes to the burden of genetic alterations.
The accumulation of these unrepaired changes can lead to cellular degeneration and a decline in organ function. Defects in DNA repair pathways associated with aging can increase the risk of age-related diseases, including neurodegenerative disorders, and contribute to increased cancer incidence in older individuals.
Factors Compromising Genetic Stability
Genetic stability is challenged by sources of DNA damage, categorized as exogenous or endogenous. Exogenous factors originate from the external environment and include agents that directly interact with DNA. Ultraviolet (UV) radiation, particularly from sunlight, is a common exogenous mutagen.
UV-B radiation can cause the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs), abnormal covalent bonds between adjacent pyrimidine bases, distorting the helix. Chemical mutagens, found in pollutants or substances like tobacco smoke, can also damage DNA by forming adducts or causing strand breaks. Ionizing radiation, such as X-rays, can induce various types of DNA damage, including deleterious double-strand breaks.
Endogenous factors arise from normal cellular processes. Errors during DNA replication are a source of internal damage; despite proofreading mechanisms, DNA polymerase can occasionally insert an incorrect nucleotide or cause small insertions or deletions. Another endogenous threat comes from reactive oxygen species (ROS), highly reactive molecules produced as byproducts of normal metabolism, such as during oxidative phosphorylation.
These ROS, including superoxide radicals and hydrogen peroxide, can cause oxidative stress, leading to damage like the oxidation of DNA bases. For example, guanine can be oxidized to 8-oxo-7,8-dihydroguanine (8-oxoG), which can mispair with adenine during replication, leading to mutations. While cells have defenses against these internal threats, persistent exposure or insufficient repair capacity can lead to an accumulation of DNA damage, compromising genetic stability.