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Reinking, H.K.* ; Kang, H.-S. ; Götz, M.J.* ; Li, H.Y.* ; Kieser, A.* ; Zhao, S.* ; Acampora, A.C.* ; Weickert, P.* ; Fessler, E.* ; Jae, L.T.* ; Sattler, M. ; Stingele, J.*

DNA structure-specific cleavage of DNA-protein crosslinks by the SPRTN protease.

Mol. Cell 80, 102-113.e6 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
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Repair of covalent DNA-protein crosslinks (DPCs) by DNA-dependent proteases has emerged as an essential genome maintenance mechanism required for cellular viability and tumor suppression. However, how proteolysis is restricted to the crosslinked protein while leaving surrounding chromatin proteins unharmed has remained unknown. Using defined DPC model substrates, we show that the DPC protease SPRTN displays strict DNA structure-specific activity. Strikingly, SPRTN cleaves DPCs at or in direct proximity to disruptions within double-stranded DNA. In contrast, proteins crosslinked to intact double- or single-stranded DNA are not cleaved by SPRTN. NMR spectroscopy data suggest that specificity is not merely affinity-driven but achieved through a flexible bipartite strategy based on two DNA binding interfaces recognizing distinct structural features. This couples DNA context to activation of the enzyme, tightly confining SPRTN's action to biologically relevant scenarios.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Repair ; Dna Structure ; Dna-protein Crosslink ; Formaldehyde ; Protease ; Spartan ; Sprtn ; Topoisomerases ; Wss1; Dvc1 C1orf124; Replication; Repair; Spartan; Damage; Phosphodiesterase; Instability; Activation; Mechanism
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1097-2765
e-ISSN 1097-4164
Journal Molecular Cell
Quellenangaben Volume: 80, Issue: 1, Pages: 102-113.e6 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants Deutsche Forschungsgemeinschaft
Ludwig-Maximilians-Universität München
Alfried Krupp von Bohlen und Halbach-Stiftung
Peter and Traudl Engelhorn Foundation
LMU -China Scholarship Council Program
International Max-Planck Research School for Molecular Life Sciences
European Research Council (ERC)
Alfried Krupp Prize for Young University Teachers - Alfried-Krupp von Bohlen und Halbach-Stiftung
European Research Council (ERC Starting Grant SOLID)
Center for Integrated Protein Science Munich (CIPSM)
DOI 10.1016/j.molcel.2020.08.003
WOS ID WOS:000576954000011
Scopus ID 85090490875
PubMed ID 32853547
Erfassungsdatum 2020-10-29
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