dc.contributor.author |
Ghosh, Arijit |
en_US |
dc.contributor.author |
Bhattacharjee, Sangheeta |
en_US |
dc.contributor.author |
Chowdhuri, Srijita Paul |
en_US |
dc.contributor.author |
MALLICK, ABHIK |
en_US |
dc.contributor.author |
Rehman, Ishita |
en_US |
dc.contributor.author |
Basu, Sudipta |
en_US |
dc.contributor.author |
Das, Benu Brata |
en_US |
dc.date.accessioned |
2019-12-24T11:53:47Z |
|
dc.date.available |
2019-12-24T11:53:47Z |
|
dc.date.issued |
2019-11 |
en_US |
dc.identifier.citation |
Science Advances, 5(11). |
en_US |
dc.identifier.issn |
2375-2548 |
en_US |
dc.identifier.uri |
http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/4247 |
|
dc.identifier.uri |
https://doi.org/10.1126/sciadv.aax9778 |
en_US |
dc.description.abstract |
A homozygous mutation of human tyrosyl-DNA phosphodiesterase 1 (TDP1) causes the neurodegenerative syndrome, spinocerebellar ataxia with axonal neuropathy (SCAN1). TDP1 hydrolyzes the phosphodiester bond between DNA 3′-end and a tyrosyl moiety within trapped topoisomerase I (Top1)-DNA covalent complexes (Top1cc). TDP1 is critical for mitochondrial DNA (mtDNA) repair; however, the role of mitochondria remains largely unknown for the etiology of SCAN1. We demonstrate that mitochondria in cells expressing SCAN1-TDP1 (TDP1H493R) are selectively trapped on mtDNA in the regulatory non-coding region and promoter sequences. Trapped TDP1H493R-mtDNA complexes were markedly increased in the presence of the Top1 poison (mito-SN38) when targeted selectively into mitochondria in nanoparticles. TDP1H493R-trapping accumulates mtDNA damage and triggers Drp1-mediated mitochondrial fission, which blocks mitobiogenesis. TDP1H493R prompts PTEN-induced kinase 1–dependent mitophagy to eliminate dysfunctional mitochondria. SCAN1-TDP1 in mitochondria creates a pathological state that allows neurons to turn on mitophagy to rescue fit mitochondria as a mechanism of survival. |
en_US |
dc.language.iso |
en |
en_US |
dc.publisher |
American Association for the Advancement of Science |
en_US |
dc.subject |
Strand Break Repair |
en_US |
dc.subject |
Topoisomerase-I Top1 |
en_US |
dc.subject |
Spinocerebellar Ataxia |
en_US |
dc.subject |
Nuclear-Dna |
en_US |
dc.subject |
Human-Cells |
en_US |
dc.subject |
Tdp1 Damage |
en_US |
dc.subject |
Enzyme |
en_US |
dc.subject |
Autophagy |
en_US |
dc.subject |
Transcription |
en_US |
dc.subject |
TOC-DEC-2019 |
en_US |
dc.subject |
2019 |
en_US |
dc.title |
SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy |
en_US |
dc.type |
Article |
en_US |
dc.contributor.department |
Dept. of Chemistry |
en_US |
dc.identifier.sourcetitle |
Science Advances |
en_US |
dc.publication.originofpublisher |
Foreign |
en_US |