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MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms

Item Type:Article
Title:MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms
Creators Name:Kozlowski, M. and Corujo, D. and Hothorn, M. and Guberovic, I. and Mandemaker, I.K. and Blessing, C. and Sporn, J. and Gutierrez-Triana, A. and Smith, R. and Portmann, T. and Treier, M. and Scheffzek, K. and Huet, S. and Timinszky, G. and Buschbeck, M. and Ladurner, A.G.
Abstract: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:DNA Damage, Heterochromatin, Histone Variants, macroH2A, PARP1
Source:EMBO Reports
ISSN:1469-221X
Publisher:EMBO Press
Volume:19
Number:10
Page Range:e44445
Date:1 October 2018
Official Publication:https://doi.org/10.15252/embr.201744445
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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