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

doi:10.7554/eLife.42988

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 journal › Article › peer-review

77 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 language	English (US)
Article number	e42988
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.42988
State	Published - Apr 2019

ASJC Scopus subject areas

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

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10.7554/eLife.42988

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@article{54a11665e23d43fe9385209124d24d10,

title = "Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription",

abstract = "How huntingtin (HTT) triggers neurotoxicity in Huntington{\textquoteright}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{\textquoteright}- 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.",

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 Hazra, {Tapas K.} and Sarkar, {Partha S.}",

note = "{\textcopyright} 2019, Gao et al.",

year = "2019",

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doi = "10.7554/eLife.42988",

language = "English (US)",

volume = "8",

journal = "eLife",

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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 K.

AU - Sarkar, Partha S.

PY - 2019/4

Y1 - 2019/4

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.

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

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