Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription

Rui Gao, Anirban Chakraborty, Charlene Geater, Subrata Pradhan, Kara L. Gordon, Jeffrey Snowden, Subo Yuan, Audrey S. Dickey, Sanjeev Choudhary, Tetsuo Ashizawa, Lisa M. Ellerby, Albert R. La Spada, Leslie M. Thompson, Tapas K. Hazra, Partha S. Sarkar

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3’- phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage- response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a potential molecular mechanism of how mutant HTT activates DNA damage-response pro-degenerative pathways and impairs transcription, triggering neurotoxicity and functional decline in HD.

Original languageEnglish (US)
Article numbere42988
JournaleLife
Volume8
DOIs
StatePublished - Apr 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Gao, R., Chakraborty, A., Geater, C., Pradhan, S., Gordon, K. L., Snowden, J., Yuan, S., Dickey, A. S., Choudhary, S., Ashizawa, T., Ellerby, L. M., La Spada, A. R., Thompson, L. M., Hazra, T. K., & Sarkar, P. S. (2019). Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. eLife, 8, [e42988]. https://doi.org/10.7554/eLife.42988