Textbook Question
Define tumor-suppressor genes. Why is a mutated single copy of a tumor-suppressor gene expected to behave as a recessive gene?
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19. Cancer Genetics
Cancer Mutations
1:45 minutesProblem 10
Textbook Question
Describe the steps by which the TP53 gene responds to DNA damage and/or cellular stress to promote cell-cycle arrest and apoptosis. Given that TP53 is a recessive gene and is not located on the X chromosome, why would people who inherit just one mutant copy of a recessive tumor-suppressor gene be at higher risk of developing cancer than those without the recessive gene?
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Step 1: Understand the role of the TP53 gene. TP53 encodes the p53 protein, which is a tumor suppressor. It plays a critical role in maintaining genomic stability by responding to DNA damage and cellular stress. When activated, p53 can induce cell-cycle arrest, allowing time for DNA repair, or trigger apoptosis (programmed cell death) if the damage is irreparable.
Step 2: Describe the mechanism of TP53 activation. Upon DNA damage or cellular stress, sensors such as ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related) kinases phosphorylate p53, stabilizing it and preventing its degradation. This allows p53 to accumulate in the nucleus, where it acts as a transcription factor to regulate the expression of target genes involved in cell-cycle arrest (e.g., CDKN1A/p21) and apoptosis (e.g., BAX, PUMA).
Step 3: Explain cell-cycle arrest and apoptosis. p53 promotes cell-cycle arrest by upregulating CDKN1A/p21, which inhibits cyclin-CDK complexes, halting the progression of the cell cycle at the G1/S checkpoint. If the damage is severe, p53 activates pro-apoptotic genes like BAX and PUMA, leading to mitochondrial dysfunction and activation of caspases, which execute apoptosis.
Step 4: Discuss the recessive nature of TP53 and cancer risk. TP53 is recessive, meaning both alleles must typically be mutated for complete loss of function. However, individuals with one mutant copy (heterozygous) are at higher risk because the remaining functional allele may be lost or mutated over time (a phenomenon called 'loss of heterozygosity'). This leaves cells without functional p53, impairing their ability to respond to DNA damage and increasing the likelihood of cancer development.
Step 5: Highlight the importance of TP53 in cancer prevention. TP53 is often referred to as the 'guardian of the genome' because of its critical role in preventing the accumulation of mutations. A single mutant copy increases susceptibility to cancer because it compromises the cell's ability to maintain genomic integrity, especially under conditions of stress or DNA damage.
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Key Concepts
Here are the essential concepts you must grasp in order to answer the question correctly.
TP53 Gene Function
The TP53 gene encodes the p53 protein, which plays a critical role in regulating the cell cycle and maintaining genomic stability. In response to DNA damage or cellular stress, p53 activates pathways that lead to cell-cycle arrest, allowing for DNA repair, or triggers apoptosis if the damage is irreparable. This function is essential for preventing the proliferation of damaged cells, thereby acting as a tumor suppressor.
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Recessive Inheritance
Recessive inheritance refers to a genetic scenario where two copies of a mutant gene are necessary for the manifestation of a trait or disease. In the case of tumor-suppressor genes like TP53, individuals with one normal and one mutant copy (heterozygous) can still express the normal function, but they are at a higher risk of developing cancer because the normal allele may be lost or inactivated, leading to a lack of tumor suppression.
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Cancer Risk and Tumor Suppressor Genes
Tumor suppressor genes, such as TP53, help control cell growth and prevent tumor formation. When one copy of a recessive tumor suppressor gene is mutated, the individual may not show symptoms initially, but they have a higher likelihood of developing cancer due to the potential for the second, normal copy to be lost or mutated over time. This loss of function can lead to uncontrolled cell division and tumor development.
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