DNA damage responses in mammalian cells and their contribution to human health disorders; the end-stage.

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All cells in our body carry the same genetic information encoded within the DNA sequence. The entire DNA sequence represents our genome. Our DNA is constantly damaged by exogenous and endogenously arising reactive chemicals. It is important that our genomes are stably maintained without any sequence changes. The maintenance of genomic stability is crucial for cancer avoidance and for normal growth and development. Genomic stability is maintained by DNA damage response mechanisms. Individuals impaired in such mechanisms have been described and can display elevated cancer predisposition, abnormal development and/or enhanced sensitivity to environmental agents such as ionizing radiation (IR). My laboratory studies the response to DNA double strand breaks (DSBs), which arise when both strands of the DNA molecule are broken in close proximity. DSBs are commonly induced by exposure to IR. The major process that repairs DSBs is called DNA non-homologous end-joining (NHEJ). The MRC has funded my laboratory for more than ten years to study the response to DSBs. The aim of this proposal is to complete the ongoing programme of work prior to my retirement. In one component of work, we have shown that the organization of DNA influences how it is repaired. DNA regions that are rarely used are more highly compacted than those that encode proteins that are required frequently. The most highly compacted DNA, called heterochromatin, is repaired more slowly than more open DNA and the repair requires additional proteins. We will seek insight into this process. The development of the immune response requires the creation of a diverse repertoire of cells that recognize different antigens. This is achieved by the creation of DSBs which are rejoined inaccurately. Curiously cells utilize NHEJ to create diversity during immune development and to maintain stability after accidental DSB formation. Patients defective in NHEJ proteins have been described and show immunodeficiency as well as IR sensitivity. They also frequently have small heads at birth demonstrating that NHEJ is required for normal neuronal development. We have characterised a mouse model for one such disorder called LIG4 Syndrome. We will complete the analysis of LIG4 mice to gain insight into the basis underlying the small head phenotype of LIG4 patients. Finally, we have also examined the basis underlying Seckel Syndrome, another disorder conferring small heads and developmental delay. We have identified genetic defects for Seckel Syndrome and will complete our current studies on the identified proteins.