Role of the BAF180 remodelling complex in transcriptional repression and DNA double strand break repair in mammalian cells.

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DNA is the genetic material which encodes the information that determines the ability of our cells to function. DNA is assembled from building blocks called base pairs, and the sequence of the base pairs is used to create the enzymes and proteins that carry out the work within a cell. Since each individual originates from a single cell, the genetic material of each cell in a body should be identical. However, cells have to go through multiple divisions to generate an organism, which necessitates that our DNA is replicated accurately. Additionally, our DNA is constantly subjected to damage, from both external and internally generated damaging agents. To maintain genetic stability, that is, the correct sequence of base pairs in our DNA, which is critical for the health of the individual and for cancer avoidance, cells have a repertoire of mechanisms that serve to repair any damage to the DNA during replication or from DNA damaging agents. A particularly dangerous lesion is when a break occurs in both DNA strands in close proximity. Such a lesion is called a DNA double strand break (DSB). If a DSB remains unrepaired, the cell will be unable to replicate and can die but, as potentially damaging, if the DSB is misrepaired, the sequence of base pairs can become changed, which is a step in the aetiology of carcinogenesis. DNA is embedded in a coat of proteins called histones, which collectively generate a protective shield to the DNA called chromatin. However, chromatin can be refractory to the repair processes. Additionally, a range of metabolic processes take place on the DNA, which can also inhibit the repair process. The genetic information encoded in the DNA is employed to generate proteins, the worker molecule of a cell. Transcription is the first step by which proteins are assembled from the genetic sequence, and transcription can be inhibitory to the DSB repair process. Thus, the cell has evolved processes that allow the chromatin to be remodelled to facilitate DSB repair and that allow transcription in the vicinity of a DSB to be inhibited. Although, we have a good understanding of the core DSB repair processes, we have very little understanding of how chromatin becomes remodelled to facilitate repair to occur nor how the repair process interface with processes such as transcription. In preliminary work, we have made the exciting observation that the PBAF complex is required for the inhibition of transcription in the vicinity of a DSB and that PBAF is required for a subcomponent of DSB repair. The aim of this proposal is to learn more about how PBAF impacts upon transcription at a DSB and how it influences the DSB repair process. This is important because a component of the PBAF complex, called BAF180, is frequently mutated in cancers of the kidney. This suggests that PBAF protects the integrity of our DNA. Thus, understanding how it impacts upon the process of DSB repair and transcription could help us understand how we are protected against cancer.