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Kinetic modelling of the UV-induced DNA damage response.

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Titel: UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and -independent pathways.
Auteur: Vrouwe, M.G., Pines, A., Overmeer, R.M., Hanada, K., and Mullenders, L.H.
Magazine: Journal of Cell Science
Titel: An immunoaffinity purification method for the proteomic analysis of ubiquitinated protein complexes.
Auteur: Schwertman, P., Bezstarosti, K., Laffeber, C., Vermeulen, W., Demmers, J.A. and Marteijn, J.A.
Magazine: Analytical Biochemistry
Titel: Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients
Auteur: Ahmad, A., Enzlin, J.H., Bhagwat, N.R., Wijgers, N., Raams, A., Appledoorn, E., Theil, A.F., Hoeijmakers, J.H., Vermeulen, W, Jaspers, N.G., Schärer, O.D., and Niedernhofer, L.J.
Magazine: PLoS Genetics
Titel: Nuclear proteins: finding and binding target sites in chromatin.
Auteur: Royen, van M.E., Zotter, A., Ibrahim, S.M., Geverts, B., and Houtsmuller, A,B.
Magazine: Chromosome Research
Titel: RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling.
Auteur: Mattiroli F, Vissers JH, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W, Marteijn JA, Sixma TK.
Magazine: Cell
Titel: A ubiquitin-binding domain in Cockayne syndrome B required for transcription-coupled nucleotide excision repair
Auteur: Anindya, R., Mari, P.O., Kristensen, U., Kool, H., Giglia-Mari, G., Mullenders, L.H., Fousteri, M., Vermeulen, W., Egly, J.M., and Svejstrup, J.Q.
Magazine: Molecular Cell
Titel: DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.
Auteur: Lans H, Lindvall JM, Thijssen K, Karambelas AE, Cupac D, Fensgård O, Jansen G, Hoeijmakers JH, Nilsen H, Vermeulen W.
Magazine: Cell Death and Differentiation
Titel: Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells
Auteur: Ogi, T., Limsirichaikul, S., Overmeer, R.M., Volker, M., Takenaka, K., Cloney, R., Nakazawa, Y., Niimi, A., Miki, Y., Jaspers, N.G., Mullenders, L.H., Yamashita, S., Fousteri, M.I., and Lehmann, A.R
Magazine: Molecular Cell
Titel: Dynamics of mammalian NER proteins
Auteur: Vermeulen, W.
Magazine: DNA Repair
Titel: DNA damage response and transcription
Auteur: Lagerwerf, S., Vrouwe, M.G., Overmeer, R.M., Fousteri, M.I., and Mullenders, L.H.
Magazine: DNA Repair
Titel: TTDA: Big impact of a small protein.
Auteur: Theil, A.F., Jan H.J. Hoeijmakers and Wim Vermeulen.
Magazine: Experimental Cell Research
Titel: SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair
Auteur: Loes van Cuijk, Gijsbert J. van Belle, Yasemin Turkyilmaz, Sara L. Poulsen, Roel C. Janssens, Arjan F. Theil, Mariangela Sabatella, Hannes Lans, Niels Mailand, Adriaan B. Houtsmuller, Wim Vermeulen & Jurgen A. Marteijn
Magazine: Nature Communications
Titel: Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts.
Auteur: Theil A.F., Nonnekens J., Wijgers N., Vermeulen W., and Giglia-Mari G.
Magazine: Molecular and Cellular Biology
Titel: Stochastic and reversible assembly of a multiprotein DNA repair complex ensures accurate target site recognition and efficient repair
Auteur: Luijsterburg, M.S., G. von Bornstaedt, A.M. Gourdin, A.Z. Politi, M.J. Mone, D.O. Warmerdam, J. Goedhart, W. Vermeulen, R. van Driel, and T. Hofer
Magazine: Journal of Cell Biology
Titel: Recognition of DNA damage by XPC coincides with disruption of the XPC–RAD23 complex
Auteur: Steven Bergink, Wendy Toussaint, Martijn S. Luijsterburg, Christoffel Dinant, Sergey Alekseev, Jan H.J. Hoeijmakers, Nico P. Dantuma, Adriaan B. Houtsmuller, and Wim Vermeulen
Magazine: Journal of Cell Biology
Titel: Replication protein A safeguards genome integrity by controlling NER incision events
Auteur: Overmeer, R.M., Moser, J., Volker, M., Kool, H., Tomkinson, A.E., van Zeeland, A.A., Mullenders, L.H., and Fousteri, M.
Magazine: Journal of Cell Biology
Titel: Transcription factor IIS impacts UV-inhibited transcription.
Auteur: Jensen, A., and Mullenders, L,H
Magazine: DNA Repair
Titel: SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair
Auteur: Loes van Cuijk, Gijsbert J. van Belle, Yasemin Turkyilmaz, Sara L. Poulsen, Roel C. Janssens, Arjan F. Theil, Mariangela Sabatella, Hannes Lans, Niels Mailand, Adriaan B. Houtsmuller, Wim Vermeulen & Jurgen A. Marteijn
Titel: Involvement of global genome repair, transcription coupled repair, and chromatin remodeling in UV DNA damage response changes during development.
Auteur: Lans, H., Marteijn, J.A., Schumacher, B., Hoeijmakers, J.H., Jansen, G., and Vermeulen, W.
Magazine: PLoS Genetics
Titel: Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality.
Auteur: Theil AF, Nonnekens J, Steurer B, Mari PO, de Wit J, Lemaitre C, Marteijn JA, Raams A, Maas A, Vermeij M, Essers J, Hoeijmakers JH, Giglia-Mari G, Vermeulen W.
Magazine: PLoS Genetics
Titel: Replication factor C recruits DNA polymerase delta to sites of nucleotide excision repair but is not required for PCNA recruitment.
Auteur: Overmeer R.M., Gourdin, A.M., Giglia-Mari, A., Kool, H., Houtsmuller, A.B., Siegal, G., Fousteri, M.I., Mullenders, L.H., and Vermeulen, W. 2010.
Magazine: Molecular and Cellular Biology
Titel: PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1.
Auteur: Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, Hensbergen P, Deelder A, de Groot A, Matsumoto S, Sugasawa K, Thoma N, Vermeulen W, Vrieling H, Mullenders L.
Magazine: Journal of Cell Biology
Titel: RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response.
Auteur: Poulsen SL, Hansen RK, Wagner SA, van Cuijk L, van Belle GJ, Streicher W, Wikström M, Choudhary C, Houtsmuller AB, Marteijn JA, Bekker-Jensen S, Mailand N.
Magazine: Journal of Cell Biology
Titel: Robustness of DNA repair through collective rate control.
Auteur: Verbruggen P, Heinemann T, Manders E, von Bornstaedt G, van Driel R, Höfer T.
Magazine: PLoS Computational Biology
Titel: Global phosphoproteome profiling reveals unanticipated networks responsive to Cisplatin treatment of embryonic stem cells.
Auteur: Pines, A., Kelstrup, C.D., Vrouwe, M.G., Puigvert, J.C., Typas, D., Misovic, B., de Groot, A., von Stechow, L., van de Water, B., Danen, E.H., Vrieling, H., Mullenders, L.H., and Olsen, J.V. 2011.
Magazine: Molecular and Cellular Biology
Titel: Nucleotide excision repair-initiating proteins bind to oxidative DNA lesions in vivo.
Auteur: Menoni H, Hoeijmakers JH, Vermeulen W. J Cell Biol. 2012 Dec 24;199(7):1037-46
Magazine: Journal of Cell Biology
Titel: UVSSA and USP7, a new couple in transcription-coupled DNA repair.
Auteur: Schwertman P, Vermeulen W, Marteijn JA.
Magazine: Chromosoma
Titel: Differential binding kinetics of replication protein A during replication and the pre- and post-incision steps of nucleotide excision repair.
Auteur: Gourdin, A.M., Loes van Cuijk, Maria Tresini, Martijn S. Luijsterburg, Alex L. Nigg, Guiseppina Giglia-Mari, Adriaan B. Houtsmuller, Wim Vermeulen and Jurgen A. Marteijn.
Magazine: DNA Repair
Titel: Influence of the live cell DNA marker DRAQ5 on chromatin-associated processes.
Auteur: Mari, P.O., Verbiest, V., Sabbioneda, S., Gourdin, A.M., Wijgers, N., Dinant, C., Lehmann, A.R., Vermeulen, W., and Giglia-Mari, G.
Magazine: DNA Repair
Titel: ATP-dependent chromatin remodeling in the DNA-damage response
Auteur: Lans H, Marteijn JA, and Vermeulen W.
Magazine: Epigenetics and Chromatin
Titel: UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair.
Auteur: Petra Schwertman, Anna Lagarou, Dick H.W. Dekkers, Anja Raams, Adriana C. van der Hoek, Charlie Laffeber, Jan H.J. Hoeijmakers, Jeroen A.A. Demmers, Maria Fousteri, Wim Vermeulen and Jurgen A. Marteijn
Magazine: Nature Genetics
Titel: Enhanced Chromatin Dynamics by FACT Promotes Transcriptional Restart after UV-Induced DNA Damage.
Auteur: Dinant C, Ampatziadis-Michailidis G, Lans H, Tresini M, Lagarou A, Grosbart M, Theil AF, van Cappellen WA, Kimura H, Bartek J, Fousteri M, Houtsmuller AB, Vermeulen W, Marteijn JA.
Magazine: Molecular Cell
Titel: Impaired repair of ionizing radiation-induced DNA damage in Cockayne syndrome cells
Auteur: Cramers, P., Verhoeven, E.E., Filon, A.R., Rockx, D.A., Santos, S.J., van der Leer, A.A., Kleinjans, J.C., van Zeeland, A.A., and Mullenders, L,H. 2011.
Magazine: Radiation Research
Titel: Human ISWI complexes are targeted by SMARCA5 ATPase and SLIDE domains to help resolve lesion-stalled transcription.
Auteur: Aydin, Ö.Z., Jurgen A. Marteijn, Crisitna Ribeiro-Silva, Aida Rodríguez López, Nils Wijgers, Godelieve Smeenk, Haico van Attikum, Raymond A. Poot, Wim Vermeulen and Hannes Lans.
Magazine: Nucleic Acid Research
Titel: Touching base with PARPs: moonlighting in the repair of UV lesions and double-strand breaks.
Auteur: Pines, A., Leon H. Mullenders, Haico van Attikum, and Martijn S. Luijsterburg.
Magazine: Trends in Biochemical sciences
Titel: Ubiquitin at work: The ubiquitous regulation of the damage recognition step of NER.
Auteur: van Cuijk, L., Wim Vermeulen and Jurgen A Marteijn
Magazine: Experimental Cell Research
Titel: Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging
Auteur: Kamenisch, Y., Fousteri, M., Knoch, J., von Thaler, A.K., Fehrenbacher, B., Kato, H., Becker, T., Dollé, M.E., Kuiper, R., Majora, M., Schaller, M., van der Horst, G.T., van Steeg, H., Röcken, M., Rapaport, D., Krutmann, J., Mullenders, L.H., and Berneburg, M.
Magazine: Journal of Experimental Medicine
Titel: ISWI chromatin remodeling complexes in the DNA damage response.
Auteur: Aydin, Ö.Z., Wim Vermeulen and Hannes Lans
Magazine: Cell Cycle
Titel: Insight in the multilevel regulation of NER.
Auteur: Dijk, M., Typa, D., Mullenders, L. and Pines, A.
Magazine: Experimental Cell Research
Titel: The Nucleus.
Auteur: Giglia-Mari G., Zotter, A., Vermeulen, W.

Verslagen


Eindverslag

Nucleotide excisie reparatie (NER) is een belangrijk proces dat een groot aantal verschillende soorten DNA schades kan reparen. De ernstige klinische gevolgen die gepaard gaan met aangeboren afwijkingen in genen die voor NER enzymen coderen, zoals vroegtijdige veroudering, extreme zonlicht gevoeligheid en een meer dan 1000 maal verhoogde kans op het verkrijgen van huidtumoren, laten het belang van NER zien. De meeste eiwitten die nodig zijn voor NER zijn bekend. Echter, hoe die eiwitten precies samenwerken en hoe de activiteit van die enzymen gecontroleerd wordt, is grotendeels onbekend. Binnen dit onderzoeksproject, werken onderzoekers van het Erasmus MC (afdelingen Genetica en Pathologie), LUMC (Genetische toxicologie) en van de UvA (SILS), nauw samen om met een multidisciplinaire onderzoeksaanpak deze vragen op te lossen. Met behulp van moderne celbiologische technieken, grotendeels ontwikkeld door de samenwerkende onderzoekers, zullen nauwkeurig de werkingssnelheden van NER-eiwitten in levende cellen in kaart worden gebracht. Deze gegevens worden gebruikt als input in een door deze onderzoekers ontwikkeld computermodel. Dit model helpt de onderzoekers om de complexe samenwerking van eiwitten en de regulatie binnen NER beter te begrijpen en mogelijke belangrijke regulatie stappen te voorspellen. Vervolgens worden deze voorspellingen getoetst met de beschikbare celbiologische en biochemische meetmethodes. Een ander belangrijke aspect binnen dit project is om met moderne zogenaamde ‘proteomics’ en ‘genomics’ technieken, nog reeds onbekende regulatoren van NER op te sporen.

Samenvatting van de aanvraag

Maintenance of genomic integrity in an environment of genotoxic stress generated by cellular metabolites and environmental agents is a prerequisite for proper cell function and of prime clinical importance in relation to the development of cancer and age-related disease. The mammalian genome is protected against genotoxic insults by a network of DNA damage response (DDR) mechanisms initiated by detection of the DNA lesions or DNA damage-induced chromatin alterations through specific sensors. The next stage in this process is the activation of a signal transduction cascade that signals to effector-molecules that control various genome-protection pathways, including DNA repair, cell cycle control, apoptosis, transcription and chromatin remodeling. Hence, full understanding of the mammalian DNA damage response does not only require insight into mechanisms of DNA repair, but also into the DNA damage signaling cascade. We focus on nucleotide excision repair (NER) as a model system to investigate various molecular events involved in activation of the DNA damage response. NER is a multiprotein repair system capable to remove a wide variety of helix-destabilising DNA lesions including UV-induced lesions. The severe clinical consequences associated with inherited NER defects including premature ageing and extreme cancer-susceptibility underscore its biological relevance. Despite detailed insight into the core NER reaction mechanism, little is known about the molecular events that initiate and regulate this process and their connection with chromatin remodeling, damage signalling, transcription control and cell cycle checkpoints. The core NER reaction has been investigated thoroughly in a previous ZonMW-subsidized collaboration. We now aim to shift our research focus to the regulatory pathways governing NER activity, including post-translational modifications of the core proteins, NER-related chromatin remodelling and DNA damage signalling. To investigate these regulatory processes we propose a multi-disciplinary approach: (i) state-of-the-art live cell microscopy to determine protein dynamics and reaction kinetics, (ii) novel microscopy assays to determine chromatin dynamics in living cells, (iii) chromatin immuno-precipitation (ChIP) of NER complexes to identify new NER factors, changes in chromatin near repair sites and chromatin remodelers involved, (iv) quantitative mass spectrometry to identify DNA damage induced post-translational modifications of NER proteins, and (v) integration of all obtained data in a comprehensive quantitative and predictive mathematical NER model, building on the recently developed kinetic NER core model. Such model-based integration will give deep insight into the in vivo NER process. It is expected that this systematic and integrating approach will result in spin-off methods to better monitor intracellular responses to therapeutic treatments that involve NER and to identify novel targets for treatment.

Onderwerpen

Kenmerken

Projectnummer:
91208031
Looptijd: 100%
Looptijd: 100 %
2010
2015
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. W. Vermeulen
Verantwoordelijke organisatie:
Erasmus MC