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Video transcript

Voiceover: Tumor suppressor genes are those genes whose protein products either have a halting effect on the regulation of the cell cycle, or they can also promote apoptosis, or sometimes both. So in other words these proteins are like big stop signs that act as safety checks to help stop the mistakes in cell division that can lead to uncontrolled cell growth and cancer. Now there are several sort of categories of tumor suppressor proteins. Those that recognize DNA damage and either repair it or initiate program cell death, apoptosis if it can't be repaired, so DNA repair proteins. Then there are those proteins that act as repressors of genes that are essential for the continuation of the cell cycle. So if these genes are actively repressed, and thus not expressed, the cell cycle does not continue on. So you have cell cycle repressors. With tumor suppressors there is this concept called the "Two-Hit Hypothesis." In which both alleles, and remember that alleles are basically the copies for a certain gene. And you have two copies for any given gene. One on the chromosome you got from your mom. And one on the chromosome you got from your dad. Now in the Two-Hit Hypothesis both alleles must be mutated before the effect is manifested. Because if only one of the alleles for the gene is damaged. Then you have this, sort of backup second copy, that can still produce the protective protein. So you need two hits. One hit for each of the alleles that you have. Another way that you can think of this is that in mutated oncogenes these alleles are typically dominant. So a mutation only one of the alleles yields the cancerous phenotype. But with a mutated tumor suppressor allele these mutations are recessive. Because both alleles must be mutated in order to lead to the cancerous phenotype. The Two-Hit Hypothesis was first proposed with cases of Retinoblastoma. Rapidly developing cancer that originates from the immature cells of the retina. The light detecting tissue of your eye. And I'll write this as pRb for Retinoblastoma protein. Now the Retinoblastoma protein prevents the cell from replicating when its DNA is damaged. And it does this by preventing progression of the cell cycle from G1 into the S phase or synthesis phase. So the Retinoblastoma protein binds and inhibits transcription factors. Which normally push the cell into the S phase. And this complex acts as a growth suppressor and so the cell remains in the G1 phase. This complex also attracts a histone deacetylase protein to the chromatin. Which reduces transcription of S phase promoting factors. And you can remember this by recalling that histone deacetylase leads to chromatin condensation. Or transcriptionally inactive chromatin. So this also further suppresses DNA synthesis. Another very well known tumor suppressor protein is the p53 protein. Homozygous loss of this protein is found in up to 65% of colon cancers, 50% of lung cancers, and also in breast cancers. So this is clearly a very critical tumor suppressor protein. And so p53 activates DNA repair proteins when DNA has sustained damage. And it can also arrest growth by holding the cell cycle hostage, if you will, at the G1 to S regulation point. And this gives DNA repair proteins some time to fix the damage and allow for continuation of the cell cycle. So specifically p53 binds DNA and activates several genes including ones that code for protein called p21, whichs binds the cyclin-CDK or cyclin-dependent kinase complex, which is actually the complex responsible for pushing the cell from the G1 to S phase in the cell cycle. P53 also functions in the initiation of apoptosis if the damage to DNA is irreparable. One significant exception to the Two-Hit rule for tumor suppressor genes is with certain mutations of the p53 gene product. Which can then result in what is called a "Dominant Negative." Meaning that a mutated p53 protein can prevent the protein product of the normal allele from functioning. So don't forget to sort of keep that in the back of your mind when you're thinking about tumor suppressor genes.