ATXN3 controls DNA replication and transcription by regulating chromatin structure

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  • Esperanza Hernández-Carralero
  • Elisa Cabrera
  • Gara Rodríguez-Torres
  • Yeray Hernández-Reyes
  • Abhay N Singh
  • Cristina Santa-María
  • José Miguel Fernández-Justel
  • Roel C Janssens
  • Jurgen A Marteijn
  • Bernd O Evert
  • Mailand, Niels
  • María Gómez
  • Kristijan Ramadan
  • Veronique A J Smits
  • Raimundo Freire

The deubiquitinating enzyme Ataxin-3 (ATXN3) contains a polyglutamine (PolyQ) region, the expansion of which causes spinocerebellar ataxia type-3 (SCA3). ATXN3 has multiple functions, such as regulating transcription or controlling genomic stability after DNA damage. Here we report the role of ATXN3 in chromatin organization during unperturbed conditions, in a catalytic-independent manner. The lack of ATXN3 leads to abnormalities in nuclear and nucleolar morphology, alters DNA replication timing and increases transcription. Additionally, indicators of more open chromatin, such as increased mobility of histone H1, changes in epigenetic marks and higher sensitivity to micrococcal nuclease digestion were detected in the absence of ATXN3. Interestingly, the effects observed in cells lacking ATXN3 are epistatic to the inhibition or lack of the histone deacetylase 3 (HDAC3), an interaction partner of ATXN3. The absence of ATXN3 decreases the recruitment of endogenous HDAC3 to the chromatin, as well as the HDAC3 nuclear/cytoplasm ratio after HDAC3 overexpression, suggesting that ATXN3 controls the subcellular localization of HDAC3. Importantly, the overexpression of a PolyQ-expanded version of ATXN3 behaves as a null mutant, altering DNA replication parameters, epigenetic marks and the subcellular distribution of HDAC3, giving new insights into the molecular basis of the disease.

Original languageEnglish
JournalNucleic Acids Research
Issue number11
Pages (from-to)5396–5413
Publication statusPublished - 2023

Bibliographical note

© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

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