The Aspartic Protease Ddi1 Contributes to DNA-Protein Crosslink Repair in Yeast

Naturally occurring or drug-induced DNA-protein crosslinks (DPCs) interfere with key DNA transactions if not repaired in a timely manner. The unique family of DPC-specific proteases Wss1/SPRTN targets DPC protein moieties for degradation, including stabilized topoisomerase-1 cleavage complexes (Top1...

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Bibliographic Details
Published in:Molecular cell 2020-03, Vol.77 (5), p.1066-1079.e9
Main Authors: Serbyn, Nataliia, Noireterre, Audrey, Bagdiul, Ivona, Plank, Michael, Michel, Agnès H., Loewith, Robbie, Kornmann, Benoît, Stutz, Françoise
Format: Article
Language:English
Subjects:
26S proteasome
Ddi1
DNA-protein crosslink
Flp recombinase
protease
RNA polymerase II
Rpb1
Top1
Wss1
yeast
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Summary:Naturally occurring or drug-induced DNA-protein crosslinks (DPCs) interfere with key DNA transactions if not repaired in a timely manner. The unique family of DPC-specific proteases Wss1/SPRTN targets DPC protein moieties for degradation, including stabilized topoisomerase-1 cleavage complexes (Top1ccs). Here, we describe that the efficient DPC disassembly requires Ddi1, another conserved predicted protease in Saccharomyces cerevisiae. We found Ddi1 in a genetic screen of the tdp1 wss1 mutant defective in Top1cc processing. Ddi1 is recruited to a persistent Top1cc-like DPC lesion in an S phase-dependent manner to assist in the eviction of crosslinked protein from DNA. Loss of Ddi1 or its putative protease activity hypersensitizes cells to DPC trapping agents independently from Wss1 and 26S proteasome, implying its broader role in DPC repair. Among the potential Ddi1 targets, we found the core component of Pol II and show that its genotoxin-induced degradation is impaired in ddi1. We propose that the Ddi1 protease contributes to DPC proteolysis. [Display omitted] •The Ddi1 aspartic protease assists in the processing of Top1-DNA covalent complexes•Ddi1 provides cellular resistance against a broad range of DNA-protein crosslinks•Ddi1 functions independently of 26S proteasome and the dedicated DPC protease Wss1•Genotoxin-induced turnover of the RNA polymerase II depends on Wss1 and Ddi1 Proteolysis facilitates the efficient disassembly of otherwise extremely toxic DNA-protein covalent crosslinks. Serbyn et al. show that the aspartic protease Ddi1 protects cells against a broad variety of such crosslinks and further investigate how Ddi1 coordinates with known proteolytic mechanisms involved in their elimination.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2019.12.007