PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease.
Proc Natl Acad Sci U S A
; 118(4)2021 01 26.
Article
em En
| MEDLINE
| ID: mdl-33468657
ABSTRACT
DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
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Processamento de Proteína Pós-Traducional
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Doença de Huntington
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Fosfotransferases (Aceptor do Grupo Álcool)
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Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina
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Enzimas Reparadoras do DNA
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Reparo do DNA
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Proteínas Inibidoras de STAT Ativados
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Proteína Huntingtina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2021
Tipo de documento:
Article