Mutations in Cell-Cycle Genes Remove the Controls on Division and Can Cause CancerThink of the cell cycle as a car with an accelerator that drives division forward and brakes that stop it.If the accelerator jams on or the brakes fail, the car speeds out of control and crashes.A mutation in a gene that controls the cell cycle does the same thing to a cell.It removes the normal control on division, so the cell divides again and again in uncontrolled cell division.This runaway growth builds a tumour and can lead to cancer.NoteThe detailed job of cyclins and CDKs in driving the cycle is covered in D2.1.15.Here the focus is on what happens when the genes behind that control are damaged.Proto-oncogenes Are the Accelerator, and a Mutation Jams It OnDefinitionProto-oncogenesProto-oncogenes are normal genes that act as the cell’s accelerator, promoting cell division when needed.From Proto-oncogene to OncogeneA proto-oncogene is a normal gene whose protein tells the cell when it is safe to divide.When it mutates it becomes an oncogene, an overactive version that keeps pushing the cell to divide even when it should not.A mutation in just one of the two gene copies is enough, so the oncogene acts in a dominant way.How the Mutation Overactivates the GenePoint mutation: a single base change makes the protein hyperactive.Gene amplification: extra copies of the gene make far too much of the protein.Chromosomal rearrangement: the gene is moved next to a strong promoter that switches it on too much.ExampleThe Ras gene is a proto-oncogene that normally passes on signals for cell growth.A mutation can lock Ras in its active form, so it keeps sending a divide signal.Tumour Suppressor Genes Are the Brakes, and a Mutation Makes Them FailTumour suppressor genes act as the brakes, holding the cell back so it does not divide too often.When a tumour suppressor gene is mutated, the brakes fail and division is no longer held in check.What These Genes Normally DoCell-cycle control: proteins like p53 halt the cycle if the DNA is damaged, giving time for repair.DNA repair: genes like BRCA1 fix errors that arise during replication.Apoptosis: if the damage cannot be fixed, they trigger programmed cell death so the faulty cell is removed.NoteMutations in tumour suppressor genes are usually recessive.Both copies of the gene must be lost before the brake stops working.What Happens When the Brakes FailUnchecked division: cells slip past checkpoints and keep dividing.Build-up of mutations: without DNA repair, further errors pile up.No apoptosis: damaged cells that should die instead survive and divide.ExampleThe p53 gene is called the guardian of the genome and is mutated in over half of human cancers.When it works, it stops the cycle to repair the DNA or triggers apoptosis if the damage is too severe.p53 in ActionApoptosis triggered if the damage to the cell is too severe.Uncontrolled Division Builds a TumourMutations in proto-oncogenes and tumour suppressor genes together remove the controls on the cell cycle.The cell then divides far too often in uncontrolled cell division.This excessive proliferation produces a mass of cells called a tumour.Tumour cells also tend to lose their specialised functions as they keep dividing.NoteA tumour is simply a mass formed by uncontrolled division.The differences between tumour types are covered in D2.1.17.Cancer Usually Needs Several Mutations, Not Just OneA single mutation is rarely enough to cause cancer.It usually takes several mutations in different cell-cycle genes to fully remove the controls on division.These mutations often build up in the same cell over many years.NoteCancer risk rises with age because mutations keep accumulating.The more mutations a cell collects, the more likely a tumour forms.Mutagens Raise the Chance of These MutationsA mutagen is an agent that increases the chance of a mutation.A mutagen that causes cancer is also called a carcinogen.Chemical: substances such as tobacco smoke or asbestos.Radiation: high-energy radiation such as X-rays or UV light.Theory of KnowledgeHow far should governments regulate substances like tobacco or industrial chemicals to lower mutagen exposure?Who should decide when the evidence linking an agent to cancer is strong enough to act on?Active recallWhat is the difference between a proto-oncogene and an oncogene?How does the mutation of a tumour suppressor gene remove control of the cell cycle?Why must both copies of a tumour suppressor gene be lost, but only one copy of a proto-oncogene?What does uncontrolled cell division produce, and what role does p53 normally play?What is a mutagen, and how does it relate to a carcinogen?
