Understanding at the molecular level the clinical consequences of defective ataxia telangiectasia and Rad3-related (ATR)

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Damage to our genetic material, DNA, occurs everyday and if left un-repaired can lead to cell death and/or cancer development. Our DNA can be damaged not only as a result of exposure to genotoxic chemicals or radiation but also indirectly, during normal cellular metabolism. For example, certain enzymes actually introduce breaks at specific locations in our DNA in certain cell types as a normal step during activation of our immune system. This allows the splicing together of distinct pieces of DNA to form new gene combinations to make specific antibodies. Several human genetic disorders exist that are defective in the normal response to DNA damage. One such disorder, Seckel syndrome, can be caused by a mutation in the ataxia telangiectasia and Rad3-related (ATR) gene. This gene creates a protein that functions as a key regulator of the normal response DNA damage. Seckel syndrome is characterised by profound growth retardation, skeletal abnormalities and a dramatically reduced head circumference which denotes a particular brain abnormality called ?microcephaly?. This suggests that the ATR protein plays some fundamental role during skeletal and brain development. What this role is has not been previously determined. This proposal aims to characterise how defective ATR impacts on these processes and results in such a severe condition as Seckel syndrome.