Deoxyribonucleic acid, commonly known as DNA, serves as the fundamental blueprint for life, carrying all the hereditary information within nearly every cell of an organism. This complex molecule is organized into a double helix structure, resembling a twisted ladder, with its rungs formed by pairs of chemical bases: adenine (A) with thymine (T), and guanine (G) with cytosine (C). The precise sequence of these bases dictates the instructions for building and maintaining an organism. DNA damage refers to any alteration to this delicate structure. Such changes can prevent DNA from functioning correctly, impacting processes like replication and transcription.
Damage from Within the Body
Even within the normal functioning of a cell, DNA can incur damage through several internal processes. One significant source is the byproduct of metabolism, particularly reactive oxygen species (ROS). These highly reactive molecules, generated during processes like cellular respiration, can chemically modify DNA bases and cause breaks in the DNA strands. For instance, oxidative DNA damage can lead to over 20 types of altered bases and single-strand breaks.
Mistakes can also arise during DNA replication, the process where a cell makes copies of its DNA before dividing. While highly accurate, DNA polymerases, the enzymes responsible for replication, are not infallible. These errors can result in incorrect base pairings or the insertion or deletion of bases, altering the genetic code. Although cells have proofreading mechanisms, some errors can still slip through.
Spontaneous chemical reactions can naturally alter DNA bases. For example, depurination involves the loss of a purine base (adenine or guanine) from the DNA backbone. This occurs frequently. Another common reaction is deamination, where an amino group is removed from a base, such as cytosine converting to uracil. While less frequent than depurination, deamination can lead to mispairing during replication if not repaired.
Damage from the Environment
External factors from the environment also contribute significantly to DNA damage. Ultraviolet (UV) radiation, primarily from the sun, is a common culprit. When UV light is absorbed by DNA, it can cause adjacent pyrimidine bases (thymine and cytosine) to form abnormal covalent bonds, known as pyrimidine dimers. These dimers distort the DNA helix and can impede proper DNA replication and transcription.
Ionizing radiation, such as X-rays and gamma rays, presents another significant external threat. This type of radiation has enough energy to directly break the DNA backbone, leading to single- and double-strand breaks. Double-strand breaks are particularly challenging for cells to repair due to the absence of a template strand. Ionizing radiation can also indirectly damage DNA by generating reactive oxygen species.
Various chemical mutagens found in the environment can also induce DNA damage. These include pollutants, components of tobacco smoke, certain industrial chemicals, and even some chemotherapy drugs. Chemical mutagens can directly modify DNA bases, insert themselves into the DNA structure, or create cross-links between DNA strands. Some can lead to mispairing or loss of bases, while others form bulky adducts on DNA.
Impact of DNA Damage
When DNA damage persists or is not repaired accurately, it can have serious consequences for cellular function and an organism’s health. Unrepaired damage or faulty repair processes can lead to permanent changes in the DNA sequence, known as mutations. While DNA damage is a structural alteration, a mutation is a change in the base sequence itself. These mutations can alter gene expression or protein function, potentially affecting cellular processes.
The accumulation of mutations and structural changes in the genome results in genomic instability. This instability means that cells have a higher propensity for further genetic alterations, which can be passed on to subsequent cell generations. Genomic instability can impair normal cellular functions. Damaged DNA can trigger cell cycle arrest, pausing cell division to allow for repair, or in cases of extensive damage, programmed cell death (apoptosis).
Persistent DNA damage is linked to the development of various diseases, with cancer being a prominent example. The accumulation of DNA lesions can contribute to tumorigenesis by increasing the likelihood of mutations that activate cancer-promoting genes or inactivate tumor-suppressing genes. Beyond cancer, unrepaired DNA damage and genomic instability also play a role in the aging process and age-related diseases.