Defective DNA strand break repair, genome instability and cancer


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Stephen C West1
1Cancer Research UK London Research Institute, South Mimms, UK

Abstract

All living organisms feature DNA repair pathways that safeguard the integrity of the genome, and mutations in proteins that mediate key events in DNA repair have been linked to genome instability and tumorigenesis. One particularly dangerous form of DNA damage occurs when the chromosomes suffer double-strand breaks and these need to be repaired efficiently in order to avoid DNA translocations or partial chromosome loss. Mutations in tumour suppressors such as BRCA2, PALB2, or BLM affect the efficiency of DNA repair by a process known as homologous recombination.

Many of the key steps of recombination have now been reconstituted with purified proteins and defined DNA substrates, leading to a good understanding of the molecular mechanism of this repair process. In particular, we have purified the BLM protein (defective in the cancer prone disease known as Bloom's Syndrome), the BRCA2 (FANCD1) and PALB2 (FANCN) tumour suppressors (also mutated in some cases of Fanconi anemia), and the newly discovered FANCP protein, also known as SLX4, and have initiated structure-function analyses to elucidate their molecular functions. How these proteins process DNA, and how they are regulated and controlled to direct the outcome of recombinational repair is now revealing unexpected insights that extend our understanding of efficient DNA repair and tumour avoidance.