Journal article
Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability
Cell, Vol.186(22), pp.4898-4919.e25
10/26/2023
DOI: 10.1016/j.cell.2023.09.008
PMCID: PMC11209935
PMID: 37827155
Abstract
Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA’s suppression of disease-associated repeat expansions, which may extend to other DNA processes.
Details
- Title: Subtitle
- Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability
- Creators
- Terence Gall-Duncan - University of TorontoJennifer Luo - University of TorontoCarla-Marie Jurkovic - Université de SherbrookeLaura A Fischer - Washington University in St. LouisKyota Fujita - Tokyo Medical and Dental UniversityAmit L Deshmukh - Hospital for Sick ChildrenRachel J Harding - University of TorontoStephanie Tran - University of TorontoMustafa Mehkary - University of TorontoVanessa Li - University of TorontoDavid E Leib - University of PennsylvaniaRan Chen - Washington University in St. LouisHikari Tanaka - Tokyo Medical and Dental UniversityAmanda G Mason - Leiden University Medical CenterDominique Lévesque - Université de SherbrookeMahreen Khan - University of TorontoMortezaali Razzaghi - University of IowaTanya Prasolava - Hospital for Sick ChildrenStella Lanni - Hospital for Sick ChildrenNozomu Sato - Hospital for Sick ChildrenMarie-Christine Caron - Université LavalGagan B Panigrahi - Hospital for Sick ChildrenPeixiang Wang - Hospital for Sick ChildrenRachel Lau - Hospital for Sick ChildrenArturo López Castel - Universitat de ValènciaJean-Yves MassonLynette Tippett - University of AucklandClinton Turner - Auckland City HospitalMaria Spies - University of IowaAlbert R La Spada - University of California, IrvineEric I Campos - University of TorontoMaurice A Curtis - University of AucklandFrançois-Michel BoisvertRichard L M Faull - University of AucklandBeverly L Davidson - University of PennsylvaniaMasayuki NakamoriHitoshi Okazawa - Tokyo Medical and Dental UniversityMarc S Wold - University of IowaChristopher E Pearson - University of Toronto
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.186(22), pp.4898-4919.e25
- DOI
- 10.1016/j.cell.2023.09.008
- PMID
- 37827155
- PMCID
- PMC11209935
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Grant note
- DOI: 10.13039/501100001700, name: Government of Japan Ministry of Education Culture Sports Science and Technology; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/501100000024, name: Canadian Institutes of Health Research; DOI: 10.13039/501100000038, name: Natural Sciences and Engineering Research Council of Canada; DOI: 10.13039/100001671, name: Hereditary Disease Foundation
- Language
- English
- Electronic publication date
- 10/05/2023
- Date published
- 10/26/2023
- Academic Unit
- Radiation Oncology; Biochemistry and Molecular Biology
- Record Identifier
- 9984482556602771
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