Abstract

In eukaryotes, genomic DNA is packaged into the nucleus primarily by association with histone proteins to form chromatin.  This structure, while necessary for compaction and chromosome segregation, is inhibitory to most processes that require access to DNA, such as transcription, replication and repair.  For this reason, cells have two powerful mechanisms for manipulating the structure of chromatin; covalent modification of histones and ATP-dependent chromatin remodelling activities.  Multiple chromatin modifying activities are involved in preventing genome instability by functioning to signal and repair damaged DNA, as well as to promote faithful chromosome segregation.  Our recent work has focused on two complexes: PBAF (also called SWI/SNF-B) and INO80.  Both of these complexes contribute to cellular functions that promote and maintain genome stability, but by different mechanisms.  Our aim is to investigate the molecular mechanisms underpinning these activities and to explore the potential interplay between these complexes in the cell.  These approaches will yield insights into how chromatin remodelling activities contribute to genome stability and prevent tumourigenesis.