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The ubiquitin-depen...
The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin
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Krastev, DB (author)
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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, J (author)
- Karolinska Institutet
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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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(creator_code:org_t)
- 2022-01-10
- 2022
- English.
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In: Nature cell biology. - : Springer Science and Business Media LLC. - 1476-4679 .- 1465-7392. ; 24:1, s. 62-
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Abstract
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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.
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- art (subject category)
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- By the author/editor
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Krastev, DB
-
Li, SD
-
Sun, YL
-
Wicks, A
-
Hoslett, G
-
Weekes, D
-
show more...
-
Badder, LM
-
Knight, EG
-
Marlow, R
-
Calvo, MP
-
Yu, L
-
Talele, TT
-
Bartek, J
-
Choudhary, J
-
Pommier, Y
-
Pettitt, SJ
-
Tutt, A
-
Ramadan, K
-
Lord, CJ
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show less...
- Articles in the publication
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Nature cell biol ...
- By the university
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Karolinska Institutet