Abstract IA18: Molecular basis for cancer susceptibility in Bloom's syndrome

Abstract

Abstract BLM is a member of the RecQ family of DNA helicases, and is the protein defective in the cancer predisposition disorder, Bloom's syndrome. This autosomal recessive disorder is also associated with fertility, immune system and skin abnormalities. BLM forms part of an evolutionarily conserved complex of proteins including Topoisomerase IIIa, RMI1 and RMI2 (collectively called the BTRR complex). The BTRR complex has a well-defined role in S-phase, but our recent studies have uncovered a novel function in mitosis. All proliferating cells must faithfully segregate their newly replicated sister chromatids during mitosis. Any perturbation of this process, arising from either endogenous or exogenous sources, can lead to cell death or chromosomal instability. We have shown previously that common fragile site loci are difficult to segregate in anaphase and, as a result, create so-called ultra-fine anaphase bridges (UFBs). These bridges are present in virtually all cells in early anaphase and are decorated along their length by a SNF2 family protein, PICH, and the BTRR complex. We hypothesize that common fragile sites fail to complete replication in S-phase, which necessitates that action of the PICH and BTRR proteins to disentangle the incompletely replicated DNA in anaphase itself. We are analyzing these processes in yeast, chicken and human cells. For example, we have generated a PICH-deficient chicken DT-40 cell mutant, and have devised a system in yeast to generate a site-specific, artificial fragile site by blocking converging replication forks. Biochemically, we are analyzing the ability of purified PICH and BTRR proteins to disentangle a DNA substrate in vitro that mimics the structure that would form as two replication forks converge. We have also recently discovered a link between the action of DNA structure-specific nuclease, MUS81-EME1, and the frequency of fragile site expression and UFB formation. Results of these studies will be discussed. Citation Format: Ian D. Hickson. Molecular basis for cancer susceptibility in Bloom's syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA18. doi:10.1158/1538-7445.CANSUSC14-IA18