FEN-1/WRN Complex in Prevention of Genetic Diseases

FEN-1/WRN 复合物预防遗传病

• 批准号: 7459899
• 负责人: L DAVID FINGER
• 金额: $ 5.2万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-26 至 2009-06-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459899
• 关键词: Amides; Binding; Biochemical; Catalysis; Chemicals; Cleaved cell; Complex; Critiques; DNA; DNA Binding; DNA Sequence; DNA Structure; DNA biosynthesis; DNA chemical synthesis; DNA-Binding Proteins; DNA-Protein Interaction; Excision; Exhibits; Flap Endonucleases; Genes; Genome; Genomics; Goals; Hereditary Disease; Heteronuclear NMR; Homologous Gene; Human; Human Genome; Huntington Disease; Incidence; Kinetics; Knock-in Mouse; Knock-out; Maintenance; Mammals; Maps; Metabolic Pathway; Modeling; Molecular; Myotonic Dystrophy; Nature; Nitrogen; Nucleotides; Okazaki fragments; Pathway interactions; Phenotype; Polymerase; Prevention; Process; Property; Proteins; Protons; RNA primers; RTH-1 Nuclease; Recruitment Activity; Resolution; Site; Spinocerebellar Ataxias; Structure; Surface; Surgical Flaps; Tertiary Protein Structure; Testing; Trinucleotide Repeats; Yeasts; endonuclease; human disease; in vivo; mutant; nuclease; pol genes; yeast genetics

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.

描述（由申请人提供）：三核苷酸重复（TNR）DNA序列存在于整个人类基因组中，并具有在复制过程中扩增的内在倾向。已知这些序列的扩增导致几种人类疾病，包括亨廷顿病、脊髓小脑性共济失调和强直性肌营养不良。由于TNR序列的性质导致的几种DNA代谢途径的错误已经被认为是TNR扩增的原因。TNR扩增的一个机制涉及冈崎片段成熟的错误。通常，5 '-瓣状核酸内切酶（FEN-1）切割在滞后链DNA合成期间产生的单链5'-瓣状DNA结构。然而，当瓣包含TNR序列时，瓣可以折叠成发夹结构，其已经显示抑制FEN-1对瓣结构的切割。因此，FEN-1不能处理TNR 5 '-发夹瓣被认为是TNR扩张的原因之一。FEN-1最近在体内显示出在TNR发夹瓣和叉DNA结构中的相似性，推测FEN-1 /WRN复合物在体内加工TNR发夹瓣结构，从而抑制哺乳动物中的TNR扩增。这一假设与酵母FEN-1基因缺失导致TNR扩增发生率的两个数量级差异的观察结果一致。此外，假设WRN的独特DNA结合性质除了刺激催化活性之外还将FEN-1活性引导至TNR发夹瓣位点。