Introduction: Genomic instability and cancer: Lessons from analysis of Bloom’s syndrome
Session type: Parallel sessions
Bloom’s syndrome (BS) is a disorder associated with short stature, sunlight sensitivity, and a greatly elevated level of cancers of all types. At the cellular level, BS is associated with genomic instability. The BS gene product, BLM, is a member of the highly conserved RecQ helicase family. BLM forms a stable complex with a set of conserved factors, including topoisomerase III and two OB-fold-containing proteins called RMI1 and RMI2 (the BTRR complex). Together, these proteins are able to disentangle intertwined DNA structures that arise during homologous recombination and DNA replication. The BTRR complex interacts with a number of other proteins, either constitutively or at specific stages of the cell cycle; most notably, with the FANCM and RIF1 proteins. FANCM is defective in one form of Fanconi anaemia, a cancer predisposition disorder associated with progressive bone marrow failure. Previously, we reported that the BTRR complex could catalyze a process called Holliday junction dissolution that promotes the faithful completion of homologous recombination events without associated genomic rearrangement. Our recent evidence indicates that the BTRR complex can also catalyze the unlinking of two DNA molecules that mimic a late-stage replication intermediate where two replication forks converge. In a search for any downstream consequences of a failure to complete the unlinking of replication and/or recombination intermediates, we identified ultra-fine DNA bridges (UFBs) in cells undergoing anaphase that had escaped detection previously because they do not contain histones or stain with widely-used DNA dyes. UFBs are more prevalent than conventional, bulky anaphase bridges and can be identified by the presence of BLM or PICH, a SNF2 family DNA translocase. UFBs derive from specific chromosomal loci; in particular, either centromeres or chromosome fragile sites. A potential mechanism by which the BTRR complex, in combination with PICH, suppresses the accumulation of anaphase bridges will be discussed.