MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms

Marek Kozlowski (1) , David Corujo (2) , Michael Hothorn (3) , Iva Guberovic (2) , 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) , Sébastien Huet (4) , Gyula Timinszky (1) , Marcus Buschbeck (2) , Andreas G Ladurner (1)

1 LMU - Ludwig-Maximilians-Universität München
2 UAB - Universitat Autònoma de Barcelona
3 EMBL - European Molecular Biology Laboratory [Heidelberg]
4 IGDR - Institut de Génétique et Développement de Rennes

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, PARP1-dependent 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 PARP1 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: PARP1; heterochromatin; histone variants; macroH2A; DNA damage

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology

Marek Kozlowski, David Corujo, Michael Hothorn, Iva Guberovic, Imke K Mandemaker, et al.. MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms. EMBO Reports, 2018, 19 (9), pp.e44445. ⟨10.15252/embr.201744445⟩. ⟨hal-01880171⟩