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DC Field | Value | Language |
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dc.citation.endPage | 11311 | - |
dc.citation.number | 19 | - |
dc.citation.startPage | 11294 | - |
dc.citation.title | NUCLEIC ACIDS RESEARCH | - |
dc.citation.volume | 49 | - |
dc.contributor.author | Park, Jumin | - |
dc.contributor.author | Lee, Jongbo | - |
dc.contributor.author | Kim, Ji-hyung | - |
dc.contributor.author | Lee, Jongbin | - |
dc.contributor.author | Park, Heeju | - |
dc.contributor.author | Lim, Chunghun | - |
dc.date.accessioned | 2023-12-21T15:08:17Z | - |
dc.date.available | 2023-12-21T15:08:17Z | - |
dc.date.created | 2021-10-03 | - |
dc.date.issued | 2021-11 | - |
dc.description.abstract | C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598(R69C) mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD. | - |
dc.identifier.bibliographicCitation | NUCLEIC ACIDS RESEARCH, v.49, no.19, pp.11294 - 11311 | - |
dc.identifier.doi | 10.1093/nar/gkab834 | - |
dc.identifier.issn | 0305-1048 | - |
dc.identifier.scopusid | 2-s2.0-85120690687 | - |
dc.identifier.uri | https://scholarworks.unist.ac.kr/handle/201301/54064 | - |
dc.identifier.url | https://academic.oup.com/nar/article/49/19/11294/6374173 | - |
dc.identifier.wosid | 000720750900037 | - |
dc.language | 영어 | - |
dc.publisher | OXFORD UNIV PRESS | - |
dc.title | ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD | - |
dc.type | Article | - |
dc.description.isOpenAccess | FALSE | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biolo | - |
dc.type.docType | Article | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | AMYOTROPHIC-LATERAL-SCLEROSIS | - |
dc.subject.keywordPlus | E3 UBIQUITIN LIGASE | - |
dc.subject.keywordPlus | QUALITY-CONTROL | - |
dc.subject.keywordPlus | REPEAT EXPANSION | - |
dc.subject.keywordPlus | HEXANUCLEOTIDE REPEAT | - |
dc.subject.keywordPlus | GGGGCC REPEAT | - |
dc.subject.keywordPlus | C9ORF72 | - |
dc.subject.keywordPlus | ELONGATION | - |
dc.subject.keywordPlus | TOXICITY | - |
dc.subject.keywordPlus | PATHWAYS | - |
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