Journal ArticleDOI
A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation.
Gyula Timinszky,Susanne Till,Paul O. Hassa,Michael Hothorn,Georg Kustatscher,Bianca Nijmeijer,Julien Colombelli,Matthias Altmeyer,Ernst H. K. Stelzer,Klaus Scheffzek,Michael O. Hottiger,Andreas G. Ladurner +11 more
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TLDR
Macrodomains are identified as modules that directly sense PARP activation in vivo and establish macroH2A histones as dynamic regulators of chromatin plasticity.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.read more
Citations
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Journal ArticleDOI
The DNA Damage Response: Making It Safe to Play with Knives
TL;DR: This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.
Journal ArticleDOI
PARP inhibition: PARP1 and beyond
TL;DR: What is known about the structures and functions of the family ofPARP enzymes are reviewed, and a series of questions that should be addressed are outlined to guide the rational development of PARP inhibitors as anticancer agents.
Journal ArticleDOI
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications
TL;DR: How the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells is outlined.
Journal ArticleDOI
Histone variants-ancient wrap artists of the epigenome
Paul B. Talbert,Steven Henikoff +1 more
TL;DR: Differences among histone variants in their stability, DNA wrapping, specialized domains that regulate access to DNA, and post-translational modifications, underlie the diverse functions that histones have acquired in evolution.
Journal ArticleDOI
The PARP Side of the Nucleus: Molecular Actions, Physiological Outcomes, and Clinical Targets
Raga Krishnakumar,W. Lee Kraus +1 more
TL;DR: The abundant nuclear enzyme PARP-1, a multifunctional regulator of chromatin structure, transcription, and genomic integrity, plays key roles in a wide variety of processes in the nucleus.
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