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

对我们的遗传物质DNA的损害每天都在发生，如果不进行修复，可能导致细胞死亡和/或癌症发展。我们的DNA不仅会因暴露于基因毒性化学物质或辐射而受损，也会在正常的细胞代谢过程中间接受损。例如，某些酶实际上会在某些细胞类型的DNA的特定位置引入断裂，这是激活免疫系统的正常步骤。这使得不同的DNA片段拼接在一起，形成新的基因组合，从而产生特定的抗体。存在几种人类遗传疾病，它们在对DNA损伤的正常反应中存在缺陷。其中一种疾病，塞克尔综合征，可能是由共济失调毛细血管扩张和rad3相关（ATR）基因突变引起的。这种基因产生一种蛋白质，这种蛋白质在DNA损伤的正常反应中起关键调节作用。塞克尔综合征的特征是严重的生长迟缓、骨骼异常和头围急剧缩小，这表明一种特殊的大脑异常，称为“小头畸形”。这表明ATR蛋白在骨骼和大脑发育过程中起着一些基本作用。这个角色是什么，以前还没有确定。本提案旨在描述ATR缺陷如何影响这些过程并导致像Seckel综合征这样严重的疾病。

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.