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

被引：88

作者：

Gao, Rui ^{[1
]}

Chakraborty, Anirban ^{[2
]}

Geater, Charlene ^{[3
,4
]}

Pradhan, Subrata ^{[1
]}

Gordon, Kara L. ^{[5
]}

Snowden, Jeffrey ^{[1
]}

Yuan, Subo ^{[6
]}

Dickey, Audrey S. ^{[5
]}

Choudhary, Sanjeev ^{[7
]}

Ashizawa, Tetsuo ^{[8
]}

Ellerby, Lisa M. ^{[9
]}

La Spada, Albert R. ^{[5
]}

Thompson, Leslie M. ^{[3
,4
,10
]}

Hazra, Tapas K. ^{[2
]}

Sarkar, Partha S. ^{[1
,6
]}

机构：

[1] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA

[2] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA

[3] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA

[4] Univ Calif Irvine, Sue & Bill Gross Stem Cell Ctr, Irvine, CA USA

[5] Duke Univ, Sch Med, Dept Neurol, Durham, NC USA

[6] Univ Texas Med Branch, Dept Neurosci Cell Biol & Anat, Galveston, TX 77555 USA

[7] Sam Houston State Univ, Dept Biochem Cell Biol & Genet, Huntsville, TX 77340 USA

[8] Houston Methodist Res Inst, Dept Neurol, Houston, TX USA

[9] Buck Inst Res Aging, Novato, CA USA

[10] Univ Calif Irvine, Dept Neurobiol & Behav, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA

来源：

ELIFE | 2019年 / 8卷

关键词：

CREB-BINDING PROTEIN; MEDIATED TRANSCRIPTION; CELL-DEATH; DISEASE; DAMAGE; GENE; ATAXIN-3; EXPRESSION; MODEL; CBP;

D O I：

10.7554/eLife.42988

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：31

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