Each cell in your body suffers 10,000 to 100,000 DNA lesions per day. But repair systems in your cells are hard at work eliminating this damage. One of the most troublesome kinds of DNA damage a cell can suffer is a double strand break - losing genetic material on one strand isn't too much of a challenge for a cell since DNA machinery can use the complementary strand to repair it, but if both strands are broken, it can be a major problem. Cells have repair mechanisms and back-up systems that kick in when double-strand breaks take place, but cancer cells, which are pros at accumulating mutations and dividing rapidly, may not have as many layers of back-up repair, making them more dependent on one repair mechanism and potentially vulnerable if that mechanism fails. At a session on Saturday morning and press conference Saturday afternoon, Graham Walker from MIT, Richard Kolodner from UCSD, and Tanya Paull of University of Texas, Austin discussed DNA repair and how understanding it could lead to cancer treatment. This was another cool topic that linked basic research using humble model organisms to profound implications for cancer in humans.
BRCA1 and BRCA2 are well-known breast cancer oncogenes involved in DNA repair. Cancer cells mutate rapidly and divide rapidly and like regular cells, must have a way of fixing double strand breaks. However, if BRCA1 or BRCA2 are mutated, a DNA repair mechanism known as homologous recombination can't take place. Cancer cells must therefore rely on a different repair mechanism known as base-excision repair. Drugs called PARP inhibitors can interrupt this latter mechanism. Dr. Paull noted that cells can survive if they lose one pathway, but not if they lose both (known as synthetic lethality). Targeting the "redundant" pathway allows researchers to specifically target cancer cells with BRCA1/BRCA2 mutations; normal cells will just switch to their "back-up" repair mechanism, but cancer cells won't have that luxury.
Dr. Kolodner reminded us that every time a cell divides and makes a copy of DNA, there's plenty of room for error. He invited journalists in the audience to imagine retyping an article - you're bound to introduce spelling mistakes. Cells need a "spell check" or mismatch repair mechanism. He also noted that many of the discoveries about DNA repair mechanisms have been made in yeast - the results have translated well into humans.
In the 1970s, researchers discovered the "SOS response" in E. coli - this allows DNA machinery to breach a DNA lesion - but the prevailing sentiment at the time was that this only took place in bacteria. Until the 1980s, DNA repair research focused on biochemical descriptions of pathways, but now the focus is on identifying genes and linking them to proteins and phenomena. The field has blossomed from biochemical descriptions to mechanistic explanations.