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Zhao, S.* ; Kieser, A.* ; Li, H.Y.* ; Reinking, H.K.* ; Weickert, P.* ; Euteneuer, S.* ; Yaneva, D.* ; Acampora, A.C.* ; Götz, M.J.* ; Feederle, R. ; Stingele, J.*

A ubiquitin switch controls autocatalytic inactivation of the DNA-protein crosslink repair protease SPRTN.

Nucleic Acids Res. 49, 902-915 (2021)
Publ. Version/Full Text Research data DOI
Open Access Gold
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Repair of covalent DNA-protein crosslinks (DPCs) by the metalloprotease SPRTN prevents genome instability, premature aging and carcinogenesis. SPRTN is specifically activated by DNA structures containing single- and double-stranded features, but degrades the protein components of DPCs promiscuously and independent of amino acid sequence. This lack of specificity is useful to target diverse protein adducts, however, it requires tight control in return, in order to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover the components and principles of a ubiquitin switch, which negatively regulates SPRTN. We demonstrate that monoubiquitylation is induced in an E3 ligase-independent manner and, in contrast to previous assumptions, does not control chromatin access of the enzyme. Data obtained in cells and in vitro reveal that monoubiquitylation induces inactivation of the enzyme by triggering autocatalytic cleavage in trans while also priming SPRTN for proteasomal degradation in cis. Finally, we show that the deubiquitylating enzyme USP7 antagonizes this negative control of SPRTN in the presence of DPCs.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Quellenangaben Volume: 49, Issue: 2, Pages: 902-915 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Institute(s) Monoclonal Antibody (IDO-MAB)
Grants ERC
Center for Integrated Protein Sciences Munich (CIPSM)
Alfried Krupp Prize for Young University Teachers - Alfried Krupp von Bohlen and Halbach-Stiftung
European Research Council [ERC Starting Grant]
International Max-Planck Research School for Molecular Life Sciences
Peter and Traudl Engelhorn Foundation
LMU-China Scholarship Council Program