Fang-Kircher S G, Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G
University of Vienna, Institute of Medical Chemistry, Austria.
Life Sci. 1999;64(18):1689-99. doi: 10.1016/s0024-3205(99)00107-1.
Although deficient DNA-repair was proposed for neurodegenerative disorders including Down Syndrome (DS), repair genes for nucleotide excision repair or X-ray repair have not been studied in brain yet. As one of the hypotheses for the pathogenesis of brain damage in DS is oxidative stress and cells of patients with DS are more susceptible to ionizing irradiation, we decided to study ERCC2, ERCC3 and XRCC1, representatives of repair genes known to be involved in the repair of oxidative DNA-damage. mRNA steady state levels of ERCC2, ERCC3, XRCC1, a transcription activator (TAF-DBP) and an elongation factor (EF1A) were determined and normalized versus the housekeeping gene beta-actin in five individual brain regions of nine controls and nine DS patients. Although different in the individual regions, DNA-repair genes were consistently higher in temporal, parietal and occipital lobes of patients with DS accompanied by comparable changes of TFA-DBP and EF1A. Our results are the first to describe DNA-repair gene patterns in human brain regions providing the basis for further studies in this area. We showed that DNA-repair genes ERCC2 and ERCC3 (excision-repair-cross-complementing-) for nucleotide excision repair and XRCC1 (X-ray-repair-cross-complementing-) for X-ray-repair, were increased at the transcriptional level with the possible biological meaning that this increase may be compatible with permanent (oxidative?) DNA damage.
尽管有人提出包括唐氏综合征（DS）在内的神经退行性疾病存在DNA修复缺陷，但核苷酸切除修复或X射线修复的相关修复基因在大脑中尚未得到研究。由于DS脑损伤发病机制的假说之一是氧化应激，且DS患者的细胞对电离辐射更敏感，我们决定研究ERCC2、ERCC3和XRCC1，这些是已知参与氧化DNA损伤修复的修复基因代表。我们测定了9名对照者和9名DS患者五个脑区中ERCC2、ERCC3、XRCC1、一种转录激活因子（TAF-DBP）和一种延伸因子（EF1A）的mRNA稳态水平，并以管家基因β-肌动蛋白进行标准化。尽管在各个脑区存在差异，但DS患者颞叶、顶叶和枕叶的DNA修复基因始终较高，同时TFA-DBP和EF1A也有类似变化。我们的结果首次描述了人类脑区的DNA修复基因模式，为该领域的进一步研究提供了基础。我们发现，参与核苷酸切除修复的DNA修复基因ERCC2和ERCC3（切除修复交叉互补）以及参与X射线修复的XRCC1（X射线修复交叉互补）在转录水平上有所增加，其可能的生物学意义在于这种增加可能与永久性（氧化性？）DNA损伤相适应。
