Main guardians of the genome: p53 and Rb
Tumor suppressor genes act as cellular brakes. Their main task is to halt proliferation and trigger programmed cell death (apoptosis) in the event of critical damage.
A key representative is the p53 gene. Normally (wild type), it responds to nuclear DNA damage by arresting the cell cycle in the G1 phase, giving the cell time for repair. If restoring the DNA structure is impossible, p53 initiates apoptosis. However, mutant p53 behaves as a dominant trait. Not only does it fail to stop division, but it also stimulates the proliferation of cells with a defective genome, leading to genome instability.
Another important antioncogene is Rb, located on chromosome 13. Its inactivation causes retinoblastoma. Tumor development requires damage to both alleles. In the hereditary form (40% of cases), the first mutation is inherited from parents (germline), while the second occurs spontaneously. In the sporadic form (60%), both mutations happen randomly in a single somatic cell.
Regulation of apoptosis and tumor survival
Malignant transformation largely depends on the balance between tumor suppressor genes and oncogenes. The general principle of carcinogenesis is the accumulation of mutations in oncogenes against the backdrop of antioncogene function loss.
Apoptosis regulation plays a huge role. For example, the bcl2 gene is a cellular oncogene with anti-apoptotic activity. Its overexpression protects tumor cells from death. A classic example is B-cell follicular lymphoma, where due to the t(14;18) chromosomal translocation, the bcl2 gene ends up in the region of actively working genes regulating immunoglobulin heavy chain synthesis. A similar apoptosis-protection mechanism is characteristic of small cell lung cancer.
Interestingly, the destruction of a tumor cell during chemo- or radiotherapy is achieved through the activation of p53 against the background of already active cellular oncogenes (such as c-fos and c-myc). If p53 is mutated and expression of bcl2 and oncogenes is elevated, the cell divides uncontrollably and the tumor progresses.
Epigenetic mechanisms and microRNAs
In addition to direct mutations, the activity of tumor suppressor genes can be suppressed by epigenetic changes—reversible modifications that occur without altering the DNA sequence.
- DNA methylation: An imbalance is observed in cancer cells. Global hypomethylation causes chromosomal instability, while selective promoter hypermethylation leads to the "silencing" of suppressor genes, acting as a full-fledged alternative to a mutation.
- Histone code: Acetylation and methylation of histone terminals alter chromatin packing density, thereby activating or repressing transcription.
A separate level of control is provided by microRNAs (miRNAs)—short non-coding molecules (~22 nucleotides) integrated into the RISC complex. They suppress gene expression at the post-transcriptional stage. In carcinogenesis, miRNAs play a dual role:
- As suppressors: their deficiency leads to the overproduction of oncoproteins.
- As oncogenes: their overexpression (5–100 fold in brain or breast tumors) blocks the function of normal tumor suppressor genes.
The miRNA expression profile is tissue-specific, which aids in tumor classification and the development of targeted therapy.
Briefly: answers to topical questions
Which tumor suppressor genes are mutated in colorectal cancer?
In colorectal cancer, the APC and TP53 (p53) genes are mutated.
- APC (APC) — this mutation is involved in the molecular genetic mechanism of carcinogenesis via the adenoma–carcinoma sequence.
- TP53 (TP53) — this mutation is also characteristic of the adenoma–carcinoma sequence, and alterations in this gene are found in almost all human tumors.
Which tumor suppressor genes are associated with hereditary breast cancer?
Hereditary breast cancer is associated with germline mutations in breast cancer predisposition genes:
- BRCA1 — the gene product is involved in DNA repair and cell cycle regulation; locus 17q21.
- BRCA2 — the gene product is involved in DNA repair and cell cycle regulation; locus 13q12.3.
- CHEK.
- NBS1.
- TP53.
What functions does the p53 protein perform in a healthy cell?
In a healthy cell, the normal ("wild-type") p53 protein functions as a transcription factor and DNA-binding protein.
- Cell cycle control — regulates the transition from the G1 to the S phase; upon DNA damage, it activates the transcription of the WAFI protein, which inactivates cyclins.
- DNA repair and synthesis — ensures the restoration of genome structure during cell cycle arrest.
- Triggering apoptosis — initiates programmed cell death if DNA damage is irreparable.
- Cell differentiation — participates in cell specialization processes.
To remember the mechanism of retinoblastoma development, imagine a car with two brake pedals (two alleles of the Rb gene). A tumor will develop only if both pedals break. If one is intact, it compensates for the braking function.
Class and exam questions
Why is mutant p53 so dangerous for the cell?
It acts as a dominant trait. Instead of stopping the division of the defective cell in the G1 phase, it stimulates its proliferation, leading to the formation of an unstable genome.
How does radiation therapy work at the molecular level?
It causes DNA damage, which activates the normal p53 gene against the background of active oncogenes (c-fos, c-myc). This combination triggers tumor cell apoptosis.
How does hereditary retinoblastoma differ from sporadic retinoblastoma?
In the hereditary form (40% of cases), the first Rb gene mutation is already present in all cells from birth, so only one spontaneous hit is needed. In the sporadic form (60%), both mutations occur randomly in a single somatic cell.
What else to study on this topic
- DNA repair mechanisms in the G1 phase of the cell cycle
- Chromosomal translocation t(14;18) in B-cell follicular lymphoma
- The role of cellular oncogenes c-fos and c-myc in carcinogenesis
- RNA-induced silencing complex (RISC) and post-transcriptional regulation
- Histone code: the effect of acetylation and methylation on transcription
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