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The ubiquitin-depen...
The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-01-10
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Springer Science and Business Media LLC,2022
Numbers
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:148555552
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http://kipublications.ki.se/Default.aspx?queryparsed=id:148555552URI
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https://doi.org/10.1038/s41556-021-00807-6DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.
Added entries (persons, corporate bodies, meetings, titles ...)
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Li, SD
(author)
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Sun, YL
(author)
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Wicks, A
(author)
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Hoslett, G
(author)
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Weekes, D
(author)
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Badder, LM
(author)
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Knight, EG
(author)
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Marlow, R
(author)
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Calvo, MP
(author)
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Yu, L
(author)
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Talele, TT
(author)
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Bartek, JKarolinska Institutet
(author)
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Choudhary, J
(author)
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Pommier, Y
(author)
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Pettitt, SJ
(author)
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Tutt, A
(author)
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Ramadan, K
(author)
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Lord, CJ
(author)
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Karolinska Institutet
(creator_code:org_t)
Related titles
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In:Nature cell biology: Springer Science and Business Media LLC24:1, s. 62-+1476-46791465-7392
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Krastev, DB
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Li, SD
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Sun, YL
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Wicks, A
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Hoslett, G
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Weekes, D
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Badder, LM
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Knight, EG
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Marlow, R
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Calvo, MP
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Yu, L
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Talele, TT
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Bartek, J
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Choudhary, J
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Pommier, Y
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Pettitt, SJ
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Tutt, A
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Ramadan, K
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Lord, CJ
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Nature cell biol ...
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Karolinska Institutet