Within each of our cells, the protein DNA topoisomerase II-binding protein 1 (TOPBP1) acts as a guardian of our genetic material. TOPBP1 is a large scaffold protein designed to interact with many other proteins inside the cell’s nucleus. Its primary responsibilities include overseeing DNA replication and regulating the cell cycle. By managing these processes, it ensures the genetic blueprint remains stable and intact, a role known as maintaining genomic stability.
The Role in DNA Maintenance
TOPBP1’s role in maintaining DNA integrity begins with DNA replication. During cell division, DNA unwinds to be copied at a structure called the replication fork. TOPBP1 helps manage and stabilize this fork, ensuring the copying process is smooth and accurate. This prevents the replication machinery from stalling or collapsing, which could otherwise introduce errors into the new DNA.
Its function extends to addressing DNA damage, including severe double-strand breaks where the DNA molecule is completely severed, which can lead to the loss of genetic information if not repaired correctly. When this damage occurs, TOPBP1 is recruited to the site to act as a platform. It brings together other repair proteins to mend the break, often after the MRE11–RAD50–NBS1 (MRN) complex signals that damage has occurred.
TOPBP1 contains multiple structural components called BRCT domains, which are protein-binding modules. These domains allow it to interact with many other proteins involved in the DNA damage response. For instance, TOPBP1 was first identified through its association with BRCA1, a protein implicated in breast cancer, underscoring its collaborative role in safeguarding the genome.
The Cell’s Emergency Brake System
When TOPBP1 detects significant DNA damage, it initiates a pause in the cell’s life cycle. This function acts as an emergency brake, halting cell division to prevent a damaged cell from multiplying. Proceeding with damaged DNA would pass dangerous genetic errors to new cells, so this pause is a form of quality control.
This halt is achieved through checkpoint activation, where TOPBP1 activates a kinase known as ATR. By activating ATR, TOPBP1 triggers a signaling cascade that stops the cell cycle, typically at the transition from the G1 to S phase or during the G2 phase. This pause provides a window of opportunity for the repair machinery, which TOPBP1 also helps assemble, to fix the DNA damage.
The checkpoint signaling pathway is a complex network, but TOPBP1’s role is direct in sensing the problem and activating this stop. Without this emergency brake, cells would continue to divide with broken or incomplete DNA, leading to widespread genomic instability.
Connection to Cancer
The failure of TOPBP1 to perform its duties is linked to cancer development. A mutated or faulty TOPBP1 gene produces a dysfunctional protein that cannot properly manage DNA repair or halt the cell cycle. Over time, this buildup of mutations can affect genes that control cell growth, leading to the uncontrolled proliferation that defines cancer.
Because of this role, TOPBP1 is considered a tumor suppressor. Its function is intertwined with other cancer-related proteins, including BRCA1, a protein whose mutation increases the risk for breast and ovarian cancer. It also interacts with the p53 tumor suppressor and the E2F-1 transcription factor, which helps regulate the cell cycle. The disruption of these partnerships by a faulty TOPBP1 can cripple the cell’s defense network.
Elevated levels of TOPBP1 are observed in various cancers, including breast, ovarian, and lung cancer. This may indicate that cancer cells are under high replicative stress and have become dependent on TOPBP1’s remaining functions to survive. However, in some contexts, TOPBP1 overexpression can also induce DNA damage and contribute to cancer, highlighting its complex role.
Therapeutic Implications
The reliance of some cancer cells on TOPBP1 makes it a target for new therapies. Researchers are developing TOPBP1 inhibitors, which are drugs designed to block the protein’s function. The strategy is to exploit the vulnerabilities of cancer cells that have other defects in their DNA damage response. Inhibiting TOPBP1 can overwhelm the cancer cell’s compromised repair systems.
This approach uses a concept known as synthetic lethality. This occurs when a defect in two proteins at the same time leads to cell death, whereas a defect in only one does not. For example, cancer cells with BRCA1 or BRCA2 mutations are already deficient in one DNA repair pathway. Using an inhibitor to block TOPBP1 can selectively kill these cancer cells while leaving healthy cells unharmed.
These inhibitors are also being investigated to enhance treatments like chemotherapy and radiation, which work by causing DNA damage. By preventing cancer cells from repairing this damage, TOPBP1 inhibitors could make these therapies more potent. While still in development, targeting TOPBP1 is a promising avenue for more precise cancer treatments.