Cited by 416Genomics and Chromatin DynamicsDNA Repair MechanismsPARP inhibition in cancer therapy

A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation

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Timinszky, Gyula, Till, Susanne, Hassa, Paul O, Hothorn, Michael, Kustatscher, Georg, Nijmeijer, Bianca, Colombelli, Julien, Altmeyer, Matthias +4 more·2009·Nature Structural & Molecular Biology

Abstract

Poly-ADP-ribosylation is a post-translational modification catalyzed by PARP enzymes with roles in transcription and chromatin biology. Here we show that distinct macrodomains, including those of histone macroH2A1.1, are recruited to sites of PARP1 activation induced by laser-generated DNA damage. Chemical PARP1 inhibitors, PARP1 knockdown and mutation of ADP-ribose-binding residues in macroH2A1.1 abrogate macrodomain recruitment. Notably, histone macroH2A1.1 senses PARP1 activation, transiently compacts chromatin, reduces the recruitment of DNA damage factor Ku70-Ku80 and alters gamma-H2AX patterns, whereas the splice variant macroH2A1.2, which is deficient in poly-ADP-ribose binding, does not mediate chromatin rearrangements upon PARP1 activation. The structure of the macroH2A1.1 macrodomain in complex with ADP-ribose establishes a poly-ADP-ribose cap-binding function and reveals conformational changes in the macrodomain upon ligand binding. We thus identify macrodomains as modules that directly sense PARP activation in vivo and establish macroH2A histones as dynamic regulators of chromatin plasticity.

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Crossref · 10.1038/nsmb.1664

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Authors
Timinszky, G., Till, S., Hassa, P. O., Hothorn, M., Kustatscher, G., Nijmeijer, B., Colombelli, J., Altmeyer, M., Stelzer, E. H. K., Scheffzek, K., Hottiger, M. O., & Ladurner, A. G.
Affiliations
  • European Molecular Biology Laboratory (DE)
  • Salk Institute for Biological Studies (US)
  • University of Zurich (CH)
Corresponding author
Ladurner, Andreas G
Venue
Nature Structural & Molecular Biology
Published
2009-08-13
Volume
16
Issue
9
Pages
923-929
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W2019637656
Cited by
416
References
43
Citations by year
2026: 8 · 2025: 6 · 2024: 13 · 2023: 9 · 2022: 25 · 2021: 22 · 2020: 25 · 2019: 14 · 2018: 27 · 2017: 32 · 2016: 28 · 2015: 24 · 2014: 32 · 2013: 44 · 2012: 44
FWCI
14.24
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
European Molecular Biology Laboratory
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
macroH2A1.1, macroH2A1.2, macrodomain, PARP1, poly(ADP-ribosyl)ation, chromatin condensation, ADP-ribose binding, Ku70/Ku80, γH2AX, DNA damage response, laser-induced DNA damage, chromatin plasticity
MeSH terms
Poly (ADP-Ribose) Polymerase-1, Chromatin, DNA Damage, Enzyme Activation, HeLa Cells, Histones, Humans, Models, Molecular, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerases, Protein Binding, RNA Processing, Post-Transcriptional, Protein Structure, Tertiary, Amino Acid Motifs, Protein Structure, Quaternary

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