tumour suppressors

Meaning: Tumour suppressor genes encode proteins that brake the cell cycle, support DNA repair, or trigger apoptosis when damage is severe. Rb holds cells at the G1/S checkpoint by binding E2F until Rb is phosphorylated. p53 is activated by DNA damage, induces p21 to halt the cycle, and promotes repair or apoptosis. When these proteins are lost, damaged cells keep dividing and accumulate mutations.

On the MCAT: Passages describe a mutation and ask whether it is loss or gain of function. Losing a tumour suppressor usually requires both alleles to be inactivated (Knudson two-hit hypothesis), so a person who inherits one defective allele is only one somatic hit away from losing function. Expect questions in which cells with nonfunctional p53 pass the G1/S checkpoint despite DNA damage and resist apoptosis.

Common confusion: Tumour suppressors are not oncogenes. Proto-oncogenes (such as Ras) promote growth, and a gain-of-function mutation in one allele can create a dominant oncogene. Tumour suppressors usually behave recessively at the cellular level, though some mutant p53 proteins interfere with normal p53 and act dominant-negatively. The mutated gene is what promotes cancer; the normal gene is protective.