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 Hazra, Partha Sarkar

Research output: Contribution to journalArticle

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)
JournaleLife
Volume8
DOIs
StatePublished - Apr 17 2019

Fingerprint

Polynucleotide 5'-Hydroxyl-Kinase
Huntington Disease
Transcription
Phosphoric Monoester Hydrolases
DNA Repair
DNA Damage
Cyclic AMP Response Element-Binding Protein
Repair
DNA
DNA Repair Enzymes
Ataxia Telangiectasia
DNA Breaks
RNA Polymerase II
Ubiquitination
Transgenic Mice
Transcriptional Activation
Proteolysis
Cell Survival
Genes
Genome

Keywords

  • DNA damage
  • DNA damage response
  • Huntington's disease
  • mouse
  • neuroscience
  • polyglutamine
  • Transcription-Coupled DNA Repair

ASJC Scopus subject areas

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

Cite this

Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. / Gao, Rui; Chakraborty, Anirban; Geater, Charlene; Pradhan, Subrata; Gordon, Kara L.; Snowden, Jeffrey; Yuan, Subo; Dickey, Audrey S.; Choudhary, Sanjeev; Ashizawa, Tetsuo; Ellerby, Lisa M.; La Spada, Albert R.; Thompson, Leslie M.; Hazra, Tapas; Sarkar, Partha.

In: eLife, Vol. 8, 17.04.2019.

Research output: Contribution to journalArticle

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, T & Sarkar, P 2019, 'Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription', eLife, vol. 8. https://doi.org/10.7554/eLife.42988
Gao, Rui ; Chakraborty, Anirban ; Geater, Charlene ; Pradhan, Subrata ; Gordon, Kara L. ; Snowden, Jeffrey ; Yuan, Subo ; Dickey, Audrey S. ; Choudhary, Sanjeev ; Ashizawa, Tetsuo ; Ellerby, Lisa M. ; La Spada, Albert R. ; Thompson, Leslie M. ; Hazra, Tapas ; Sarkar, Partha. / Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. In: eLife. 2019 ; Vol. 8.
@article{e91ea197645e47d7a879ac489e46d6e7,
title = "Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription",
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.",
keywords = "DNA damage, DNA damage response, Huntington's disease, mouse, neuroscience, polyglutamine, Transcription-Coupled DNA Repair",
author = "Rui Gao and Anirban Chakraborty and Charlene Geater and Subrata Pradhan and Gordon, {Kara L.} and Jeffrey Snowden and Subo Yuan and Dickey, {Audrey S.} and Sanjeev Choudhary and Tetsuo Ashizawa and Ellerby, {Lisa M.} and {La Spada}, {Albert R.} and Thompson, {Leslie M.} and Tapas Hazra and Partha Sarkar",
year = "2019",
month = "4",
day = "17",
doi = "10.7554/eLife.42988",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription

AU - Gao, Rui

AU - Chakraborty, Anirban

AU - Geater, Charlene

AU - Pradhan, Subrata

AU - Gordon, Kara L.

AU - Snowden, Jeffrey

AU - Yuan, Subo

AU - Dickey, Audrey S.

AU - Choudhary, Sanjeev

AU - Ashizawa, Tetsuo

AU - Ellerby, Lisa M.

AU - La Spada, Albert R.

AU - Thompson, Leslie M.

AU - Hazra, Tapas

AU - Sarkar, Partha

PY - 2019/4/17

Y1 - 2019/4/17

N2 - 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.

AB - 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.

KW - DNA damage

KW - DNA damage response

KW - Huntington's disease

KW - mouse

KW - neuroscience

KW - polyglutamine

KW - Transcription-Coupled DNA Repair

UR - http://www.scopus.com/inward/record.url?scp=85066457238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066457238&partnerID=8YFLogxK

U2 - 10.7554/eLife.42988

DO - 10.7554/eLife.42988

M3 - Article

VL - 8

JO - eLife

JF - eLife

SN - 2050-084X

ER -