Defective repair of topoisomerase I induced chromosomal damage in Huntington's disease.
Cell Mol Life Sci
; 79(3): 160, 2022 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-35224690
ABSTRACT
Topoisomerase1 (TOP1)-mediated chromosomal breaks are endogenous sources of DNA damage that affect neuronal genome stability. Whether TOP1 DNA breaks are sources of genomic instability in Huntington's disease (HD) is unknown. Here, we report defective 53BP1 recruitment in multiple HD cell models, including striatal neurons derived from HD patients. Defective 53BP1 recruitment is due to reduced H2A ubiquitination caused by the limited RNF168 activity. The reduced availability of RNF168 is caused by an increased interaction with p62, a protein involved in selective autophagy. Depletion of p62 or disruption of the interaction between RNAF168 and p62 was sufficient to restore 53BP1 enrichment and subsequent DNA repair in HD models, providing new opportunities for therapeutic interventions. These findings are reminiscent to what was described for p62 accumulation caused by C9orf72 expansion in ALS/FTD and suggest a common mechanism by which protein aggregation perturb DNA repair signaling.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Huntington
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Ubiquitina-Proteína Ligases
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Reparo do DNA
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Quebras de DNA
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Proteína Sequestossoma-1
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Proteína 1 de Ligação à Proteína Supressora de Tumor p53
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article