Research - Institute of Genetics - Genome Instability and Carcinogenesis Unit - DNA Damage and Nuclear Dynamics Research Group

Gyula TIMINSZKY
senior research associate

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Szilvia JUHÁSZ research associate
Adrián Imre KÓSZÓ laboratory assistant
Bendegúz Viktor ORLOVSZKY laboratory assistant

THE REGULATION OF CHROMATIN STRUCUTRE AND NUCLEAR DYNAMICS UPON DNA DAMAGE BY ADP-RIBOSYLATION

Genome integrity is crucial for all living organisms. If damaged DNA is not promptly repaired, the mutations ultimately lead to the development of cancer. Defective repair can also cause immunodeficiency, neurodegenerative disorders and premature ageing. The range of DNA lesions require diverse signaling and repair pathways to shape the DNA damage response. This involves changes in nuclear dynamics including alterations in chromatin structure, nucleocytoplasmic transport and protein activities.




ADP-ribosylation is one of the earliest post-translational modifications appearing upon DNA damage. Its effects are numerous. One of its functions is to relax chromatin at the sites of DNA damage, facilitating the access of DNA repair processes to the lesions. Our findings indicate that nuclear dynamics, mRNA metabolism and chromosome organization strongly depend on nuclear ADP-ribosylation reactions and their crosstalk with other signaling pathways. Its deregulation impairs DNA repair and is implicated in cancer. At the bedside, the inhibition of ADP-ribosylation by drugs is used to treat cancer with certain gene mutations.




Our research goal is to characterize novel molecular mechanisms that regulate the DNA damage response, including nucleocytoplasmic transport, mRNA metabolism and chromatin architecture. We study novel cancer relevant mutations that are sensitive to ADP-ribosylation inhibitors, which could be potentially used to treat tumors carrying such mutations. Furthermore, we investigate the molecular basis of a DNA damage-induced nuclear export mechanism that regulates ADP-ribose metabolism.




Selected publications

Kozlowski M, Corujo D, Hothorn M, Guberovic I, Mandemaker IK, Blessing C, Sporn J, Gutierrez-Triana A, Smith R, Portmann T, Treier M, Scheffzek K, Huet S, Timinszky G, Buschbeck M, Ladurner AG., MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms. EMBO Reports. 2018 Sep 3. pii: e44445. doi:0.15252/embr.201744445.

Smith R, Timinszky G., 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 R, Sellou H, Chapuis C, Huet S*, Timinszky G.*, CHD3 and CHD4 recruitment and chromatin remodeling activity at DNA breaks is promoted by early poly(ADP-ribose)-dependent chromatin relaxation. Nucleic Acids Research. 2018 Jul 6;46(12):6087-6098.

Singh HR, Nardozza AP, Möller IR, Knobloch G, Kistemaker HAV, Hassler M, Harrer N, Blessing C, Eustermann S, Kotthoff C, Huet S, Mueller-Planitz F, Filippov DV, Timinszky G, Rand KD, Ladurner AG., A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene. Molecular Cell. 2017 Dec 7;68(5):860-871.e7.

Lebeaupin T, Smith R, Huet S, Timinszky G., Poly(ADP-Ribose)-Dependent Chromatin Remodeling in DNA Repair. Methods in Molecular Biology. 2017;1608:165-183.

Golia B, Moeller GK, Jankevicius G, Schmidt A, Hegele A, Preißer J, Tran ML, Imhof A, Timinszky G., ATM induces MacroD2 nuclear export upon DNA damage. Nucleic Acids Research. 2017 Jan 9;45(1):244-254.

Sellou H, Lebeaupin T, Chapuis C, Smith R, Hegele A, Singh HR, Kozlowski M, Bultmann S, Ladurner AG, Timinszky G*, Huet S*., 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.

Barkauskaite E, Jankevicius G, Ladurner AG, Ahel I, Timinszky G., The recognition and removal of poly(ADP)ribose signals. FEBS Journal. 2013 Aug;280(15):3491-507.

Czarna A, Berndt A, Singh HR, Grudziecki A, Ladurner AG, Timinszky G, Kramer A, Wolf E., Crystal structures of Drosophila Cryptochrome and mouse Cryptochrome1: insights into circadian function. Cell 2013 Jun 6;153(6):1394-405.

Jankevicius G, Hassler M, Golia B, Rybin V, Zacharias M, Timinszky G*, Ladurner AG*., A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nature Structural & Molecular Biology. 2013 Apr;20(4):508-14.

Sharifi R*, et al., Ladurner AG*, Timinszky G*, Williams RS*, Ahel I*., Deficiency of a terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. The EMBO Journal. 2013 Mar 12;32(9):1225-37.

Ali AAE*, Timinszky G*, Arribas-Bosacoma R, Kozlowski M, Hassler M, Hassa PO, Ladurner AG, Pearl LH, Oliver AW., The zinc-finger domains of PARP1 cooperate to recognise DNA strandbreaks – implications for PARP1 activation at sites of DNA damage. Nature Structural & Molecular Biology. 2012 Jun 10;19(7):685-92.

Timinszky G*, Till S*, Hassa PO*, Hothorn M*, Kustatscher G, Nijmeijer B, Colombelli J, Altmeyer M, Stelzer EH, Scheffzek K, Hottiger MO, Ladurner AG., A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nature Structural & Molecular Biology. 2009 Sep;16(9):923-9.

Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, Washburn MP, Florens L, Ladurner AG, Conaway JW, Conaway RC., Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Proc Natl Acad Sci USA. 2009 Aug 18;106(33):13770-4.

Timinszky G*, Tirián L*, Nagy FT, Tóth G, Perczel A, Kiss-László Z, Boros I, Clarke P R and Szabad J., The Importin- P446L dominant negative mutant protein loses RanGTP binding ability and blocks the formation of intact nuclear envelope. Journal of Cell Science. 2002 Apr 15;115(Pt 8):1675-87.