scholarly journals The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency

Cell Reports ◽  
2020 ◽  
Vol 32 (5) ◽  
pp. 107985 ◽  
Author(s):  
Marco Gatti ◽  
Ralph Imhof ◽  
Qingyao Huang ◽  
Michael Baudis ◽  
Matthias Altmeyer
Author(s):  
Dragomir B. Krastev ◽  
Shudong Li ◽  
Yilun Sun ◽  
Andrew J. Wicks ◽  
Gwendoline Hoslett ◽  
...  

AbstractPoly (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.


2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 5540-5540 ◽  
Author(s):  
Karina Dahl Steffensen ◽  
Rikke Fredslund Andersen ◽  
Anders Kristian Moeller Jakobsen

Oncotarget ◽  
2015 ◽  
Vol 6 (13) ◽  
pp. 10746-10758 ◽  
Author(s):  
Jessica Frankum ◽  
Pavel Moudry ◽  
Rachel Brough ◽  
Zdenek Hodny ◽  
Alan Ashworth ◽  
...  

2015 ◽  
Vol 58 ◽  
pp. 83-100 ◽  
Author(s):  
Selena Gimenez-Ibanez ◽  
Marta Boter ◽  
Roberto Solano

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.


Author(s):  
Leilani M. Chirino ◽  
Suresh Kumar ◽  
Mariko Okumura ◽  
David E. Sterner ◽  
Michael Mattern ◽  
...  

2019 ◽  
Vol 18 (11) ◽  
pp. 814-814 ◽  
Author(s):  
Asher Mullard
Keyword(s):  

Sign in / Sign up

Export Citation Format

Share Document