A gene is a fundamental unit of heredity, carrying instructions for building and maintaining an organism, primarily through protein production. Among the many genes, TOP2A encodes a protein significant in basic cellular processes. Its function centers on managing the complex structure of DNA, an activity fundamental to cell health and division.
Normal Function of TOP2A
The TOP2A gene produces an enzyme called DNA topoisomerase II alpha, a protein that manages the intricate physical structure of DNA. DNA is a very long and twisted molecule, which can become supercoiled or intertwined during normal cellular activities. DNA topoisomerase II alpha works to resolve these topological challenges, ensuring the DNA remains accessible and functional.
This enzyme operates by creating a temporary double-strand break in the DNA molecule, allowing another segment of DNA to pass through the created gap. Following this passage, the enzyme then reseals the broken DNA strands, relieving tension and untangling the DNA. This precise cutting and rejoining mechanism is particularly important during DNA replication, when the cell’s entire genetic material must be accurately copied.
Beyond replication, DNA topoisomerase II alpha is also involved in chromosome condensation, which is the process where DNA is tightly packed into compact structures before cell division. It further assists in chromatid separation, ensuring that the duplicated chromosomes are correctly pulled apart into two new daughter cells. The activity of TOP2A increases, peaking during the G2 and M phases of the cell cycle, aligning with periods of significant DNA organization and cell division. Without proper TOP2A function, cells cannot divide accurately, leading to potential errors in genetic distribution.
TOP2A’s Role in Cancer
The precise functions of TOP2A in managing DNA become highly relevant in the context of cancer, a disease characterized by uncontrolled cell division. Cancer cells proliferate at an accelerated rate, demanding increased activity from enzymes involved in DNA replication and chromosome segregation. This heightened cellular activity often leads to an overexpression of the TOP2A gene, meaning the cancer cells produce higher amounts of the DNA topoisomerase II alpha protein.
This overexpression of TOP2A contributes directly to the rapid growth and multiplication of malignant cells. By efficiently untangling and managing the DNA, the elevated TOP2A levels help cancer cells navigate the stresses associated with their fast-paced replication and transcription. This allows them to maintain genomic stability despite their rapid division, supporting tumor progression.
In many cancer types, including hepatocellular carcinoma, breast cancer, colon cancer, lung adenocarcinoma, and ovarian cancer, increased TOP2A expression is frequently observed. This altered expression can serve as an indicator for certain cancers and is often associated with more aggressive disease behavior. Studies have linked high TOP2A levels to a less favorable prognosis in various malignancies, including kidney renal clear cell carcinoma, brain lower grade glioma, and pancreatic adenocarcinoma.
The gene’s altered activity or excessive presence supports the sustained proliferation that defines cancerous growth. Research has further shown that reducing TOP2A levels can inhibit oncogenesis, emphasizing its role in tumor development.
Targeting TOP2A in Cancer Treatment
Understanding TOP2A’s significant role in the uncontrolled growth of cancer cells has led to the development of chemotherapy drugs designed to interfere with its function. These medications, known as topoisomerase II inhibitors, specifically target the DNA topoisomerase II alpha protein. Their mechanism of action involves stabilizing the temporary double-strand breaks that TOP2A creates in DNA.
By preventing TOP2A from resealing these DNA breaks, these drugs cause an accumulation of damaged DNA within cancer cells. This extensive DNA damage disrupts essential processes like DNA replication and transcription. The inability to properly repair these breaks triggers pathways that lead to cell cycle arrest and ultimately, apoptosis.
Examples of widely used topoisomerase II inhibitors include etoposide, doxorubicin, and epirubicin. These agents are employed in the treatment of a range of cancers, such as breast cancer, lung cancer, testicular cancer, lymphomas, and leukemias. The strategy of targeting TOP2A exemplifies a broader principle in cancer therapy: disrupting a protein or gene that is heavily involved in the rapid cell division characteristic of cancer can be an effective way to stop tumor growth and eliminate malignant cells.