FEN-1/WRN Complex in Prevention of Genetic Diseases

描述（由申请人提供）：三核苷酸重复（TNR） DNA序列出现在整个人类基因组中，并且在复制过程中具有内在的扩展倾向。已知这种序列的扩展会导致几种人类疾病，包括亨廷顿氏病、脊髓小脑性共济失调和肌强直性营养不良。由于TNR序列的性质，一些DNA代谢途径中的错误被认为是TNR扩增的原因。TNR扩展的一种机制涉及冈崎片段成熟过程中的错误。正常情况下，5'-flap核酸内切酶（fin -1）会切割滞后链DNA合成过程中产生的单链5'-flap DNA结构。然而，当皮瓣包含TNR序列时，皮瓣可以折叠成发夹结构，这种结构已被证明可以抑制FEN-1对皮瓣结构的切割。因此，FEN-1无法处理tnr5 '-发夹瓣被认为是TNR膨胀的原因之一。最近在体内研究显示FEN-1在TNR发夹瓣和叉DNA结构上具有相似性，假设FEN-1 /WRN复合物在体内加工TNR发夹瓣结构，从而抑制哺乳动物TNR的扩展。这一假设与酵母FEN-1基因的缺失导致TNR扩增发生率的一个或两个数量级差异的观察结果是一致的。此外，据推测，除了刺激催化活性外，WRN独特的DNA结合特性还引导FEN-1活性到达TNR发夹瓣位点。

DESCRIPTION (provided by applicant): Tri-nucleotide repeat (TNR) DNA sequences occur throughout the human genome and have an intrinsic propensity to expand during replication. Expansion of such sequences is known to result in several human diseases, including Huntington's disease, spinocerebellar ataxia, and myotonic dystrophy. Errors in several DNA metabolic pathways due to the nature of TNR sequences have been implicated as the cause for TNR expansion. One mechanism for TNR expansion involves errors in Okazaki fragment maturation. Normally, 5'-flap endonuclease (FEN-1) cleaves the single stranded 5'-flap DNA structures generated during lagging-strand DNA synthesis. However, when the flap contains a TNR sequence, the flap can fold into a hairpin structure that has been shown to inhibit FEN-1 cleavage of the flap structures. Therefore, the inability of FEN-1 to process TNR 5'-hairpin-flaps is proposed to be one cause of TNR expansion. FEN-1 has recently been shown in vivo to proc similarities in TNR hairpin flap and fork DNA structures, it is hypothesized that the FEN-1 /WRN complex processes TNR hairpin flap structures in vivo, thereby suppressing TNR expansions in mammals. This hypothesis is consistent with the observation that deletion of the yeast FEN-1 gene results in critique one a two orders of magnitude difference in the incidence of TNR expansions. Furthermore, it is hypothesized that the unique DNA binding properties of WRN guide FEN-1 activity to TNR hairpin flap sites in addition to stimulating catalytic activity.