Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis

Anirban Chakraborty, Nisha Tapryal, Tatiana Venkova, Joy Mitra, Velmarini Vasquez, Altaf H. Sarker, Sara Duarte-Silva, Weihan Huai, Tetsuo Ashizawa, Gourisankar Ghosh, Patricia MacIel, Partha S. Sarkar, Muralidhar L. Hegde, Xu Chen, Tapas K. Hazra

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by CAG (encoding glutamine) repeat expansion in the Ataxin-3 (ATXN3) gene. We have shown previously that ATXN3-depleted or pathogenic ATXN3-expressing cells abrogate polynucleotide kinase 3'-phosphatase (PNKP) activity. Here, we report that ATXN3 associates with RNA polymerase II (RNAP II) and the classical nonhomologous end-joining (C-NHEJ) proteins, including PNKP, along with nascent RNAs under physiological conditions. Notably, ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair of a 3'-phosphate-containing terminally gapped, linearized reporter plasmid. The missing sequence at the terminal break site was restored in the recircularized plasmid in control cells by using the endogenous homologous transcript as a template, indicating ATXN3's role in PNKP-mediated error-free C-NHEJ. Furthermore, brain extracts from SCA3 patients and mice show significantly lower PNKP activity, elevated p53BP1 level, more abundant strand-breaks in the transcribed genes, and degradation of RNAP II relative to controls. A similar RNAP II degradation is also evident in mutant ATXN3-expressing Drosophila larval brains and eyes. Importantly, SCA3 phenotype in Drosophila was completely amenable to PNKP complementation. Hence, salvaging PNKP's activity can be a promising therapeutic strategy for SCA3.

Original languageEnglish (US)
Pages (from-to)8154-8165
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Apr 7 2020


  • ATXN3
  • DNA double-strand break repair
  • PNKP
  • RNA-templated TC-NHEJ
  • Spinocerebellar ataxia type-3

ASJC Scopus subject areas

  • General


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