NBS1 is a protein that helps maintain the health and stability of our cells. It functions within the cell to safeguard DNA from various forms of damage. This protein ensures that cells can grow and divide correctly, preserving the integrity of genetic material.
The Role of NBS1 in DNA Repair
DNA, the genetic blueprint found within every cell, carries the instructions for all cellular activities and organism development. Maintaining the integrity of this DNA is paramount, as damage can lead to errors that disrupt normal cellular function. Cells are constantly exposed to agents that can harm DNA, ranging from environmental factors like radiation to internal metabolic byproducts. To counteract this constant assault, cells possess intricate DNA repair mechanisms.
NBS1 is a component of the MRE11-RAD50-NBS1 (MRN) complex. This complex is an initial responder to severe DNA damage, particularly double-strand breaks, where both strands of the DNA helix are severed. The MRN complex quickly accumulates at these damage sites.
Once recruited to a double-strand break, NBS1 facilitates the activation of cellular signaling pathways that coordinate the DNA damage response. It interacts with other proteins, such as ATM, MDC1, and γ-H2AX, which are involved in forming repair foci at the damaged DNA sites. NBS1 helps to recruit the MRE11 nuclease to these sites, an enzyme involved in processing the broken DNA ends. This precise coordination is part of a larger process called homologous recombination repair, a high-fidelity pathway that uses an undamaged DNA template to accurately fix the break.
Beyond double-strand breaks, NBS1 also contributes to other repair pathways, including base excision repair, which addresses common types of DNA damage like oxidized or alkylated bases. It influences the activation of proteins like PARP1, involved in this repair process. By participating in these diverse repair mechanisms and coordinating cell cycle checkpoints, NBS1 helps ensure that damaged DNA is repaired before cell division or that the cell cycle is paused to prevent error propagation.
Nijmegen Breakage Syndrome
Nijmegen Breakage Syndrome (NBS) is a rare, inherited genetic condition directly linked to mutations in the NBS1 gene, also known as NBN. This syndrome typically arises when an individual inherits two altered copies of the NBS1 gene, one from each parent, following an autosomal recessive inheritance pattern. The genetic mutations result in a dysfunctional or absent NBS1 protein, impairing the body’s ability to effectively repair DNA damage. This impairment leads to chromosomal instability, a hallmark feature of the disorder.
Microcephaly, or an unusually small head size, is a common feature of Nijmegen Breakage Syndrome, often apparent from birth and sometimes progressing. Growth retardation is also observed, with affected individuals typically growing slowly during infancy and early childhood, remaining shorter than their peers. They may also exhibit characteristic facial features, including a sloping forehead, a prominent nose, and large ears.
A significant health concern for those with NBS is immunodeficiency. They often have abnormally low levels of immune system proteins, such as immunoglobulin G (IgG) and immunoglobulin A (IgA), along with a shortage of T cells. This compromised immune system leads to recurrent infections, particularly affecting the respiratory tract. Additionally, intellectual development can be affected, with some individuals experiencing delayed development and a decline in cognitive abilities after early childhood, often resulting in mild to moderate intellectual disability.
A heightened susceptibility to cancer represents another serious aspect of Nijmegen Breakage Syndrome. Individuals with NBS are at a significantly increased risk of developing various cancers, particularly non-Hodgkin lymphoma, which often manifests before the age of 15. Other malignancies reported include brain tumors, such as medulloblastoma and glioma, and rhabdomyosarcoma. The cells of NBS patients also show an elevated sensitivity to ionizing radiation, making certain medical imaging procedures, like X-rays and CT scans, less desirable. Women with NBS may experience premature ovarian failure, leading to infertility.
NBS1 and Its Connection to Cancer
Properly functioning DNA repair mechanisms defend against cancer development. When DNA repair systems are compromised, errors in the genetic code can accumulate, leading to genomic instability. This instability can drive uncontrolled cell growth and tumor formation. NBS1 plays a direct part in this protective system, and its dysfunction can have serious implications for cancer predisposition.
NBS1 is recognized as a tumor suppressor protein, meaning it helps to prevent the uncontrolled proliferation of cells. Proteins with this role typically function by regulating cell division, ensuring that cells only divide when appropriate and that their DNA is free of errors. When the NBS1 protein is compromised due to genetic alterations, the cell’s ability to repair DNA damage, especially double-strand breaks, is diminished. This impairment allows DNA errors to persist and accumulate within the genome.
The accumulation of unrepaired DNA damage and the resulting genomic instability can lead to the acquisition of mutations that promote cancerous transformation. These mutations can activate genes that drive cell growth or inactivate other tumor suppressor genes, tipping the cellular balance towards malignancy. For instance, individuals who are carriers of a single altered copy of the NBS1 gene, while not having Nijmegen Breakage Syndrome, may still face an increased risk for certain types of cancers, such as breast cancer in women and prostate cancer in men.
Beyond the link to Nijmegen Breakage Syndrome, alterations in NBS1 have been observed in various sporadic cancers. Studies have investigated NBS1 variants and their association with increased risk in cancers like ovarian cancer, oral squamous cell carcinoma, head and neck cancer, uveal melanoma, gastric cancer, and colorectal cancer. The presence of NBS1 mutations or changes in its expression can contribute to the development or progression of these malignancies.