| Title: |
Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7 |
| Authors: |
Switonski, Pawel M; Delaney, Joe R; Bartelt, Luke C; Niu, Chenchen; Ramos-Zapatero, Maria; Spann, Nathanael J; Alaghatta, Akshay; Chen, Toby; Griffin, Emily N; Bapat, Jaidev; Sopher, Bryce L; La Spada, Albert R |
| Source: |
Cell Reports, vol 37, iss 9 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2021 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
Biological Sciences; Genetics; Neurodegenerative; Brain Disorders; Rare Diseases; Stem Cell Research; Human Genome; Neurosciences; Eye Disease and Disorders of Vision; 2.1 Biological and endogenous factors; Neurological; Acetylation; Animals; Ataxin-7; Cerebellar Diseases; DNA Repair; Female; Histones; Humans; Male; Mice; Neurons; Peptides; Spinocerebellar Ataxias; ChIP-seq; DNA damage; cerebellum; epigenetic dysregulation; neurodegeneration; polyglutamine |
| Description: |
A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt4043s7nk; https://escholarship.org/uc/item/4043s7nk; https://escholarship.org/content/qt4043s7nk/qt4043s7nk.pdf |
| DOI: |
10.1016/j.celrep.2021.110062 |
| Availability: |
https://escholarship.org/uc/item/4043s7nk; https://escholarship.org/content/qt4043s7nk/qt4043s7nk.pdf; https://doi.org/10.1016/j.celrep.2021.110062 |
| Rights: |
CC-BY |
| Accession Number: |
edsbas.8BC81B45 |
| Database: |
BASE |