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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gao, R; Chakraborty, A; Geater, C; Pradhan, S; Gordon, KL; Snowden, J; Yuan, S; Dickey, AS; Choudhary, S; Ashizawa, T; Ellerby, LM; La Spada, AR; Thompson, LM; Hazra, TK; Sarkar, PS

Published Date

  • April 17, 2019

Published In

Volume / Issue

  • 8 /

PubMed ID

  • 30994454

Pubmed Central ID

  • PMC6529219

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.42988


  • eng

Conference Location

  • England