Links Between Defective DNA Strand Break Repair and Genome Instability in Fanconi Anemia

Abstract SCI-2

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. Homologous recombination provides an important DNA repair pathway that is needed for the restoration and restart of broken replication forks, for the rejoining of chromosome/chromatid breaks, and for the processing of DNA cross-links. Mutations in genes that encode a variety of recombination proteins are linked to breast cancers and to heritable diseases such as Bloom syndrome (BS) and Fanconi anemia (FA). In recent work, we purified the BLM protein (defective in BS), the BRCA2 (FANCND1) and PALB2 (FANCN) tumor suppressors (mutated in some cases of FA), 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 tumor avoidance.