I’ve been fascinated by DNA and genetics since reading Jurassic park as a kid. Later, when I started with studies I couldn't wait until I was ready to engage in actual course on genetics. At that time my attention was drawn to DNA mismatch repair (MMR). A highly conserved mechanism, which exists in every alive cell and its primary role is to detect mismatches in DNA that will become mutations if not corrected prior cell divides.
Mismatch repair mechanism consist of rather simple steps. First, MSH2-MSH6 detect mismatch. Second, MLH1-PMS2 is engaged and that signals EXOI to cut out mismatch. New gap in DNA strand is re-sythetized by DNA polymerase.
Mismatch repair mechanism consist of rather simple steps. First, MSH2-MSH6 detects mismatch. Second, MLH1-PMS2 is engaged and that signals EXOI to cut out mismatch. New gap in DNA strand is re-sythetized by DNA polymerase.
Taken high conservation from bacteria to humans, somebody would say if you mess up with MMR life would not be possible, but… none of MMR genes when inactivated are lethal, nevertheless inactivation of even just one of two gene copies will speed up cancer development. A syndrome named after Henry Lynch is associated with inherited mutations in MMR genes. Individuals with inherited mutations in MMR genes have predisposition to develop mainly gastrointestinal cancers and women endometrial cancer.
Why is that? Well, many would say isn’t it obvious? Deficient mismatch repair leads to increased mutation rate which at the end causes cancer. I encounter this answer again and again. But increased mutability isn’t necessarily a bad thing. Without mutations life wouldn’t evolve. So why is it then that MMR deficiency is a shortcut to cancer? A less known function of MMR, and quite often shadowed by mutator phenotype, is its role in signalling apoptosis or cell death.
Healthy cells when faced with irreparable mismatch, and DNA damage in general, will either enter senescence (something like retirement, cell is still alive but not dividing anymore), or undergo apoptosis - death. MMR deficient cells, will gather more mismatches because of obvious reasons, but these cells will not undergo senescence neither trigger apoptosis. They will divide and mismatches will become mutations, of which some mutation combinations will be lethal for cell, some will live. The latter is just matter of statistics and combinatorics which combination will evolve into cancer.
In other words, inactive MMR is a shortcut to cancer because MMR deficient cells have selective growth advantage over healthy cells, and mutator phenotype is just speeding variability of cells.
Most chemotherapeutic drugs work on principle to induce apoptosis in cancer cells, but that strategy does not work in MMR deficient cancer cells, because they are unable to signal apoptosis. At present moment only gene therapy, which would restore MMR activity, accompanied by cytostatic would be efficient approach. In light of not-that-successful experiments and quite high risks of gene therapy, my opinion is that understanding mechanisms by which MMR signals apoptosis in greater detail would give a clue towards new drugging aproaches for MMR deficient cancers.