<i>RFC1</i>AAGGG pentanucleotide repeats form parallel G-quadruplex: structural implications for aberrant molecular cascades in CANVAS
Abstract A pentanucleotide repeat expansion (PRE) of (AAGGG)nin the replication factor C subunit 1 (RFC1) gene is recently identified as the genetic cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), and also linked to several other neurodegenerative disorders including the Parkinson’s disease. However, the molecular mechanism by whichRFC1PRE drives pathology remains poorly understood. Here, for the first time we discovered and determined the high-resolution structures of parallel G-quadruplex formed by AAGGG repeats within the pathogenicRFC1PRE, revealing an intriguing conformational plasticity at the 3’-termi that allows stacking of multiple G4s. We further identify a molecular mechanism by which the DNA G4 inRFC1PRE impedes polymerase processivity leading to replication stalling and transcription inhibitionin vitroin a repeat-length-dependent manner, and the transcription inhibition could partially contribute to a reduced gene expression in cells. Our results demonstrate that the DNA G-quadruplex ofRFC1PRE participate in aberrant molecular cascades, and provide an unprecedented high-resolution structural target to discover helicases and ligands that resolve the pathogenic G4 for therapeutic intervention..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 18. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Yang [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.08.06.552146 |
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| PPN (Katalog-ID): |
XBI040449750 |
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| 520 | |a Abstract A pentanucleotide repeat expansion (PRE) of (AAGGG)nin the replication factor C subunit 1 (RFC1) gene is recently identified as the genetic cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), and also linked to several other neurodegenerative disorders including the Parkinson’s disease. However, the molecular mechanism by whichRFC1PRE drives pathology remains poorly understood. Here, for the first time we discovered and determined the high-resolution structures of parallel G-quadruplex formed by AAGGG repeats within the pathogenicRFC1PRE, revealing an intriguing conformational plasticity at the 3’-termi that allows stacking of multiple G4s. We further identify a molecular mechanism by which the DNA G4 inRFC1PRE impedes polymerase processivity leading to replication stalling and transcription inhibitionin vitroin a repeat-length-dependent manner, and the transcription inhibition could partially contribute to a reduced gene expression in cells. Our results demonstrate that the DNA G-quadruplex ofRFC1PRE participate in aberrant molecular cascades, and provide an unprecedented high-resolution structural target to discover helicases and ligands that resolve the pathogenic G4 for therapeutic intervention. | ||
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| 700 | 1 | |a Yan, Zhenzhen |4 aut | |
| 700 | 1 | |a Hou, Jianing |4 aut | |
| 700 | 1 | |a Wan, Liqi |4 aut | |
| 700 | 1 | |a Yi, Jie |4 aut | |
| 700 | 1 | |a Guo, Pei |0 (orcid)0000-0001-7760-5786 |4 aut | |
| 700 | 1 | |a Han, Da |0 (orcid)0000-0002-0804-2964 |4 aut | |
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