The molecular basis and regulation of the DNA damage-induced nuclear export of the human MacroD2 protein
Final Report Abstract
Accurate and timely DNA damage repair involves the integration of a large number of signals. Genomic instability, a common characteristic of cancers, is often caused by the impaired response and coordination of vital signaling pathways upon DNA damage. Phosphorylation and poly(ADP-ribosyl)ation (PARylation) are important signals, so called post-translational modifications upon DNA damage. MacroD2, one of the enzymes that can fully remove the PAR signal from proteins, emerges as a regulator of the crosstalk between phosphorylation and PARylation. Mutations of MacroD2 have been associated with both cancers and neurological disorders. We found that MacroD2 rapidly recruits to damage sites in response to local PARylation, but is exported from the nucleus – where the DNA is found – upon its phosphorylation by the DNA damage-induced kinase ATM (Ataxia telangiectasia mutated). Understanding the molecular functions of disease relevant proteins should help develop novel therapeutic strategies in the future.
Publications
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PARP1 and CBP lose their footing in cancer. Nature Structural & Molecular Biology. 2014 Nov; 21(11):947-8
Timinszky, Gyula & Ladurner, Andreas G.
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Chromatin dynamics at DNA breaks: what, how and why? AIMS Biophysics. 2015 Sept 10; 2(4):458-75
Lebeaupin, Théo; Sellou, Hafida; Timinszky, Gyula & Huet, Sébastien
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Poly-ADP-ribosylation signaling during DNA damage repair. Frontiers in Bioscience. 2015 Jan 1; 20:440-57
Golia B, Singh HR, Timinszky G.
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The histone chaperone sNASP binds a conserved peptide motif within the globular core of histone H3 through its TPR repeats. Nucleic Acids Research. 2015 Dec 15. pii: gkv1372
Bowman, Andrew; Lercher, Lukas; Singh, Hari R.; Zinne, Daria; Timinszky, Gyula; Carlomagno, Teresa & Ladurner, Andreas G.
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ATM induces MacroD2 nuclear export upon DNA damage. Nucleic Acids Research. 2017 Jan 9;45(1):244-254.3
Golia, Barbara; Moeller, Giuliana Katharina; Jankevicius, Gytis; Schmidt, Andreas; Hegele, Anna; Preißer, Julia; Tran, Mai Ly; Imhof, Axel & Timinszky, Gyula
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The poly(ADP-ribose)-dependent chromatin remodeler Alc1 induces local chromatin relaxation upon DNA damage. Molecular Biology of the Cell. 2016 Dec 1;27(24):3791-3799
Sellou, Hafida; Lebeaupin, Théo; Chapuis, Catherine; Smith, Rebecca; Hegele, Anna; Singh, Hari R.; Kozlowski, Marek; Bultmann, Sebastian; Ladurner, Andreas G.; Timinszky, Gyula & Huet, Sébastien
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Monitoring Poly(ADP-Ribosyl)ation in Response to DNA Damage in Live Cells Using Fluorescently Tagged Macrodomains. Methods in Molecular Biology. 2018;1813:11-24
Smith, Rebecca & Timinszky, Gyula
