Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans
碩士 === 國立中正大學 === 分子生物研究所 === 104 === Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by an expanded CTG repeat in the DMPK gene. The transcribed CUG repeats recruit the RNA binding protein, MBNL, to form RNA foci in the nucleus. This results in sequestration of MBNL and d...
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ndltd-TW-104CCU000610102017-05-14T04:32:08Z http://ndltd.ncl.edu.tw/handle/81614097240714961206 Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans 線蟲Dna-2是擴增CUG重複序列的修飾基因 WENG,PEI-YU 翁佩鈺 碩士 國立中正大學 分子生物研究所 104 Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by an expanded CTG repeat in the DMPK gene. The transcribed CUG repeats recruit the RNA binding protein, MBNL, to form RNA foci in the nucleus. This results in sequestration of MBNL and disruption of the alternative splicing of its downstream targets. To explore the molecular mechanism and the possible therapeutic targets of DM1, transgenic C. elegans expressing reporter-tagged CUG repeats was established. The validated DM1 phenotype in this system could be alleviated by decreasing the expression of expanded CUG RNA. To screen for the genetic modifiers of the DM1 phenotype, the DM1 worms were fed with bacteria clones from the C. elegans RNAi library. I found that knockdown of Dna-2 specifically reduced the expression of the expanded CUG repeats, but not the short CUG repeats. Dna-2 RNAi treatment also partially rescued the phenotypes of DM1 worms including shortened life span, decreased motility rate and abnormal muscle morphology . These data indicated that knockdown of Dna-2 suppressed the DM1 phenotype. In order to confirm if Dna2 plays a suppressive role in CUG RNA toxicity in the mammalian cells, I used similar approach to suppress Dna2 expression in C2C12-CUG200 cells. Decreased expression of Dna2 could rescue differentiation defect caused by the CUG repeats. In conclusion, Dna2 can function as a genetic modifier of expanded CUG repeats and is required for its toxicity not only in C. elegans but also in C2C12 cells. HSIAO,KUANG-MING 蕭光明 2016 學位論文 ; thesis 77 zh-TW |
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碩士 === 國立中正大學 === 分子生物研究所 === 104 === Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by an expanded CTG repeat in the DMPK gene. The transcribed CUG repeats recruit the RNA binding protein, MBNL, to form RNA foci in the nucleus. This results in sequestration of MBNL and disruption of the alternative splicing of its downstream targets. To explore the molecular mechanism and the possible therapeutic targets of DM1, transgenic C. elegans expressing reporter-tagged CUG repeats was established. The validated DM1 phenotype in this system could be alleviated by decreasing the expression of expanded CUG RNA. To screen for the genetic modifiers of the DM1 phenotype, the DM1 worms were fed with bacteria clones from the C. elegans RNAi library. I found that knockdown of Dna-2 specifically reduced the expression of the expanded CUG repeats, but not the short CUG repeats. Dna-2 RNAi treatment also partially rescued the phenotypes of DM1 worms including shortened life span, decreased motility rate and abnormal muscle morphology . These data indicated that knockdown of Dna-2 suppressed the DM1 phenotype. In order to confirm if Dna2 plays a suppressive role in CUG RNA toxicity in the mammalian cells, I used similar approach to suppress Dna2 expression in C2C12-CUG200 cells. Decreased expression of Dna2 could rescue differentiation defect caused by the CUG repeats. In conclusion, Dna2 can function as a genetic modifier of expanded CUG repeats and is required for its toxicity not only in C. elegans but also in C2C12 cells.
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author2 |
HSIAO,KUANG-MING |
author_facet |
HSIAO,KUANG-MING WENG,PEI-YU 翁佩鈺 |
author |
WENG,PEI-YU 翁佩鈺 |
spellingShingle |
WENG,PEI-YU 翁佩鈺 Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans |
author_sort |
WENG,PEI-YU |
title |
Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans |
title_short |
Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans |
title_full |
Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans |
title_fullStr |
Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans |
title_full_unstemmed |
Dna-2 is a genetic modifier of the expended CUG repeats in C. elegans |
title_sort |
dna-2 is a genetic modifier of the expended cug repeats in c. elegans |
publishDate |
2016 |
url |
http://ndltd.ncl.edu.tw/handle/81614097240714961206 |
work_keys_str_mv |
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