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FEN-1/WRN Complex in Prevention of Genetic Diseases

FEN-1/WRN Complex in Prevention of Genetic Diseases
FEN-1/WRN 复合物预防遗传病
批准号：
7112507
负责人：
L DAVID FINGER
金额：
$4.88万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
项目状态：
已结题
起止时间：
2006-06-26 至 2009-06-25
来源：
https://reporter.nih.gov/project-details/7112507
关键词：
DNAgeneticshumanmutantnucleotidespreventionyeasts

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英文摘要
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.
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FEN-1/WRN Complex in Prevention of Genetic Diseases
FEN-1/WRN Complex in Prevention of Genetic Diseases
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