DNA, the genetic blueprint within nearly every cell, holds life’s instructions. This intricate molecule can suffer damage, disrupting its function. One type is DNA crosslinking, where abnormal chemical bonds form within the DNA molecule. These crosslinks significantly impact how cells operate, affecting processes from growth to repair.
What is DNA Crosslinking
DNA crosslinking is the formation of a covalent bond between two components of the DNA molecule. This bonding can occur in different configurations. One type is an intrastrand crosslink, where the bond forms within a single strand of the DNA double helix. Here, two adjacent or nearby bases on the same strand become abnormally connected.
Another type is an interstrand crosslink (ICL), which involves a covalent bond forming between opposite strands of the DNA double helix. Imagine the two intertwined ladders of DNA suddenly becoming glued together at a specific point. These ICLs are disruptive because they physically block the strands from separating, a process necessary for DNA to be read or copied.
How DNA Crosslinking Occurs
DNA crosslinking can be triggered by various agents. Exogenous agents include components in cigarette smoke, such as acrolein and crotonaldehyde. Industrial chemicals like formaldehyde and glutaraldehyde, often used as disinfectants or preservatives, can also induce crosslinks within DNA.
Therapeutic agents, such as some chemotherapeutic drugs, are designed to cause DNA crosslinks. Medications like cisplatin, cyclophosphamide, and mitomycin C form these bonds in cancer cells, disrupting their growth and division. Psoralens, plant-derived compounds, are another example; when activated by ultraviolet A (UVA) light, they form crosslinks, a property used in treating skin conditions like psoriasis.
Beyond external sources, the body’s own metabolic processes can generate endogenous agents that cause DNA crosslinks. Normal cellular metabolism produces reactive molecules, such as aldehydes like acetaldehyde (a byproduct of alcohol breakdown) and malondialdehyde (formed during lipid peroxidation). These byproducts can react with DNA, leading to crosslink formation. Oxidative stress, an imbalance between free radicals and antioxidants, can also indirectly contribute by creating a reactive environment within cells.
Cellular Consequences and Repair Mechanisms
DNA crosslinks pose a threat to cellular function because they physically obstruct two fundamental processes: DNA replication and transcription. During replication, DNA strands must separate to be copied. A crosslink acts as a barrier, halting the replication machinery. This blockage prevents cells from accurately duplicating their genetic material, which is necessary for cell division and growth.
Similarly, DNA crosslinks interfere with transcription, the process where DNA’s genetic information is copied into RNA to make proteins. Enzymes responsible for reading the DNA sequence cannot bypass a crosslink, disrupting gene expression and affecting the production of cellular proteins. If these crosslinks remain unrepaired, cells face consequences. Unresolved DNA damage can trigger cell cycle arrest, stopping cell division to allow time for repair.
If the damage is too extensive or cannot be fixed, the cell may initiate programmed cell death, known as apoptosis, to prevent the propagation of damaged DNA. Persistent unrepaired crosslinks can also lead to mutations, which may contribute to cellular dysfunction or disease development. To counteract these threats, cells have evolved intricate repair mechanisms.
One such pathway is Nucleotide Excision Repair (NER), which primarily removes bulky DNA lesions and can be involved in the initial steps of interstrand crosslink repair. For interstrand crosslinks, Homologous Recombination (HR) is a high-fidelity repair pathway. HR uses a homologous DNA template, typically the sister chromatid, to accurately repair the damaged DNA segment.
A specialized pathway, the Fanconi Anemia pathway, plays a role in detecting and initiating the repair of interstrand crosslinks. This pathway involves a complex network of proteins that recognize the crosslink, recruit other repair factors, and facilitate the unhooking and removal of the damaged segment, often working in conjunction with HR. Translesion Synthesis (TLS) offers a “last resort” mechanism, where specialized DNA polymerases can bypass a crosslink, allowing replication to continue. However, TLS is often error-prone and can introduce mutations, making it a less desirable, but sometimes necessary, repair option.
Role in Medicine and Disease
The ability of certain agents to induce DNA crosslinks is leveraged in cancer treatment. Chemotherapeutic drugs like cisplatin are designed to create these links within the DNA of rapidly dividing cancer cells. The goal is to accumulate so much DNA damage that the cancer cells’ repair mechanisms are overwhelmed, leading them to undergo programmed cell death. This strategy is effective because many cancer cells often have compromised DNA repair pathways, making them more susceptible to the effects of crosslinking agents than healthy cells.
Conversely, defects in the body’s natural DNA crosslink repair pathways are directly linked to specific genetic disorders. Fanconi Anemia is an example of such a disease, where individuals inherit mutations in genes that are part of the Fanconi Anemia pathway. Their cells are unable to properly repair interstrand crosslinks, leading to an accumulation of DNA damage. This impaired repair capacity manifests as increased sensitivity to crosslinking agents, progressive bone marrow failure, and an elevated risk of developing various cancers, including acute myeloid leukemia and head and neck squamous cell carcinoma.