FEN-1/WRN Complex in Prevention of Genetic Diseases

FEN-1/WRN 复合物预防遗传病

• 批准号: 7270471
• 负责人: L DAVID FINGER
• 金额: $ 5.04万
• 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/7270471
• 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，并在复制过程中具有固有的扩张倾向。众所周知，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强直性肌营养不良。由于TNR序列的性质，一些DNA代谢途径中的错误被认为是TNR扩张的原因。TNR扩增的一种机制涉及Okazaki片段成熟的错误。正常情况下，5‘-翻盖内切酶(FEN-1)切割滞后链DNA合成过程中产生的单链5’-翻盖DNA结构。然而，当该瓣包含TNR序列时，该瓣可以折叠成发夹结构，该发夹结构已被证明可以抑制该瓣结构的Fen-1切割。因此，FEN-1不能加工TNR 5‘-发夹状皮瓣是TNR扩张的原因之一。最近，Fen-1在体内被证明在TNR发夹结构和分叉DNA结构中具有相似性，推测Fen-1/WRN复合体在体内处理TNR发夹结构，从而抑制哺乳动物的TNR扩张。这一假设与酵母fen-1基因缺失导致TNR扩张发生率两个数量级的差异的观察结果是一致的。此外，假设WRN独特的DNA结合特性除了刺激催化活性外，还将FEN-1活性引导到TNR发夹状瓣部位。