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MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms.

EMBO Rep. 2018 Oct;19(10). Epub 2018 Sep 03
Marek Kozlowski 1 , David Corujo 2 , Michael Hothorn 3 , Iva Guberovic 4 , Imke K Mandemaker 1 , Charlotte Blessing 1 , Judith Sporn 3 , Arturo Gutierrez-Triana 3 , Rebecca Smith 1 , Thomas Portmann 3 , Mathias Treier 3 , Klaus Scheffzek 3 , Sebastien Huet 5 , Gyula Timinszky 1 , Marcus Buschbeck 6 , Andreas G Ladurner 7
Marek Kozlowski 1 , David Corujo 2 , Michael Hothorn 3 , Iva Guberovic 4 , Imke K Mandemaker 1 , Charlotte Blessing 1 , Judith Sporn 3 , Arturo Gutierrez-Triana 3 , Rebecca Smith 1 , Thomas Portmann 3 , Mathias Treier 3 , Klaus Scheffzek 3 , Sebastien Huet 5 , Gyula Timinszky 1 , Marcus Buschbeck 6 , Andreas G Ladurner 7
+ et al

[No authors listed]

Author information
  • 1 Biomedical Center, Physiological Chemistry, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
  • 2 PhD Programme of Genetics, Universitat de Barcelona, Barcelona, Spain.
  • 3 European Molecular Biology Laboratory, Heidelberg, Germany.
  • 4 Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • 5 Univ Rennes, CNRS, Structure fédérative de recherche Biosit, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France.
  • 6 Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain.
  • 7 Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität München, Munich, Germany.

摘要


MacroH2A histone variants suppress tumor progression and act as epigenetic barriers to induced pluripotency. How they impart their influence on chromatin plasticity is not well understood. Here, we analyze how the different domains of macroH2A proteins contribute to chromatin structure and dynamics. By solving the crystal structure of the macrodomain of human macroH2A2 at 1.7 Å, we find that its putative binding pocket exhibits marked structural differences compared with the macroH2A1.1 isoform, rendering macroH2A2 unable to bind ADP-ribose. Quantitative binding assays show that this specificity is conserved among vertebrate macroH2A isoforms. We further find that macroH2A histones reduce the transient, chromatin relaxation that occurs in living cells upon DNA damage through two distinct mechanisms. First, macroH2A1.1 mediates an isoform-specific effect through its ability to suppress activity. Second, the unstructured linker region exerts an additional repressive effect that is common to all macroH2A proteins. In the absence of DNA damage, the macroH2A linker is also sufficient for rescuing heterochromatin architecture in cells deficient for macroH2A.

KEYWORDS: DNA damage, PARP1, heterochromatin, histone variants, macroH2A