論文 - 詳細
| RRC ID | 53355 |
|---|---|
| 著者 | Scheibye-Knudsen M, Tseng A, Borch Jensen M, Scheibye-Alsing K, Fang EF, Iyama T, Bharti SK, Marosi K, Froetscher L, Kassahun H, Eckley DM, Maul RW, Bastian P, De S, Ghosh S, Nilsen H, Goldberg IG, Mattson MP, Wilson DM 3rd, Brosh RM Jr, Gorospe M, Bohr VA. |
| タイトル | Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. |
| ジャーナル | Proc Natl Acad Sci U S A |
| Abstract |
Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response. |
| 巻・号 | 113(44) |
| ページ | 12502-12507 |
| 公開日 | 2016-11-1 |
| DOI | 10.1073/pnas.1610198113 |
| PII | 1610198113 |
| PMID | 27791127 |
| PMC | PMC5098674 |
| MeSH | Cell Line, Tumor Cockayne Syndrome / genetics Cockayne Syndrome / metabolism DNA Damage DNA Helicases / genetics* DNA Helicases / metabolism DNA Repair DNA Repair Enzymes / genetics* DNA Repair Enzymes / metabolism DNA, Neoplasm / chemistry DNA, Neoplasm / genetics* DNA, Neoplasm / metabolism DNA, Ribosomal / genetics G-Quadruplexes Gene Knockdown Techniques Humans Neuroblastoma / genetics Neuroblastoma / metabolism Neuroblastoma / pathology Poly (ADP-Ribose) Polymerase-1 / genetics Poly (ADP-Ribose) Polymerase-1 / metabolism Poly-ADP-Ribose Binding Proteins / genetics* Poly-ADP-Ribose Binding Proteins / metabolism Transcription Factors / genetics* Transcription Factors / metabolism Transcription, Genetic* |
| IF | 9.412 |
| 引用数 | 25 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 16 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm4539 |