The TP53 gene provides instructions for making the tumor protein p53. This protein functions as a transcription factor, regulating the expression of other genes and playing a central role in preventing tumor formation. A typical human cell contains two copies of the TP53 gene, inheriting one copy from each parent. The proper function of both copies is necessary for maintaining genomic integrity and protecting the body from disease.
The Number of Copies and Location
Humans are diploid organisms, meaning most cells contain two complete sets of chromosomes. The TP53 gene resides on an autosome (non-sex chromosome), which is why individuals possess two copies. Specifically, the gene is located on the short arm of chromosome 17, at band 17p13.1.
These two copies are known as alleles and serve as the blueprints for producing the p53 protein. The presence of a pair of functional genes acts as a biological safeguard for cellular control.
The Role of p53 as the Guardian of the Genome
The protein product of the TP53 gene is often called the “guardian of the genome” due to its role in maintaining cellular DNA stability. Its primary function is to act as a molecular sensor, monitoring the cell for stress like DNA damage or oncogene activation. When significant damage occurs, p53 levels rapidly increase and the protein becomes activated.
Once activated, p53 works as a transcription factor to determine the cell’s fate. It initiates cell cycle arrest at the G1 phase checkpoint before the cell can replicate its DNA. P53 achieves this by promoting the transcription of the gene encoding p21, which inhibits the cell cycle machinery. This halting of division provides time for DNA repair mechanisms to correct the damage.
If the DNA damage is successfully repaired, p53 levels fall, and the cell proceeds with division. If the damage is too extensive, p53 shifts its focus to programmed cell death, or apoptosis. P53 induces apoptosis by activating the expression of pro-apoptotic genes, such as those in the BCL-2 family like Bax and Bak. The ability of p53 to either pause the cell for repair or execute it makes it a powerful tumor suppressor. This mechanism ensures that cells with potentially cancerous mutations are eliminated.
Inherited Defects in p53 Copy Number
While most people inherit two functional TP53 copies, some are born with a genetic predisposition to cancer due to an inherited defect in one copy. Li-Fraumeni Syndrome (LFS) is a rare hereditary condition where individuals inherit a germline mutation in one TP53 allele. This means every cell starts with only one functional copy of the gene.
This inherited defective copy represents the “first hit” in the two-hit hypothesis of tumor suppression. This condition significantly increases the lifetime risk of developing various cancers, often at a young age. Although the remaining functional copy can initially compensate, the individual is highly susceptible to cancer-causing events.
For a tumor to form in an LFS patient, the remaining healthy copy must be inactivated, known as Loss of Heterozygosity (LOH). This LOH event constitutes the “second hit,” where the sole functional copy is lost, mutated, or silenced. Once both copies are non-functional, p53 protective mechanisms fail, allowing the damaged cell to divide unchecked and form a tumor.
Acquired Mutations and Cancer Development
Most cancers are caused by acquired somatic mutations in the TP53 gene that occur later in life, not inherited defects like LFS. These mutations arise in non-germline cells due to environmental factors, such as carcinogens or UV radiation, or errors during DNA replication. TP53 is the single most frequently mutated gene across all human cancers, with a mutation rate exceeding 50% in many tumor types.
The acquired mutations are predominantly missense mutations, which are single-base changes often occurring within the protein’s DNA-binding domain. These mutant p53 proteins lose their tumor-suppressing function and can also exert a dominant-negative effect.
The dominant-negative effect means the defective p53 interferes with the remaining functional p53 produced by the healthy allele. Functional p53 must assemble into a four-part complex (tetramer); a single mutant component can destabilize or disable the entire structure. This acquired functional loss of both copies allows cells to bypass checkpoints, ignore DNA damage, and evade apoptosis, leading to uncontrolled proliferation and cancer development.