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Understanding the structure and mechanism of macromolecular machines that regulate chromatin dynamics

Dale Wigley

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Wellcome Trust (WT)
Eukaryotic genomes are packaged into nucleosomes in which the DNA is wrapped around histone octamers, that in turn form higher order structures (chromatin) within which the nucleosomes are packed together. While this arrangement of the genetic material adds a level of organisation and stability, it also creates problems for processes that need to access DNA such as transcription, replication and repair. For example, the DNA damage response involves a whole slew of changes to chromatin that are orchestrated during DNA repair. This has made the regulation of chromatin structure and dynamics a central focus for understanding a wide range of fundamental biological processes that involve the genetic material. As we learn more about chromatin regulation it is becoming clear how much morethere is to understand, particularly at a molecular and mechanistic level. How do proteins slide nucleosomes around so that proteins can access the DNA? How are nucleosomes assembled and disassembled? How is damage detected within nucleosomes? What signals recruit remodellers to nucleosomes that are damaged? As we begin to unveil these processes, we are discovering fascinating and intricate, multi-subunit proteinmachines that carry out these complex tasks in a coordinated fashion. Although the sheer complexity and size of many of the protein machines that deal with chromatin can appear daunting, we need to be able to understand these processes at a molecular level to trulyunderstand how things work, how they go wrong and how we might interfere with them in a specific manner to control disease.

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